Review ArticleImmunomodulatory Effects of Chitotriosidase Enzyme

Mohamed A Elmonem12 Lambertus P van den Heuvel13 and Elena N Levtchenko1

1Department of Pediatric Nephrology amp Growth and Regeneration University Hospitals Leuven KU Leuven UZ Herestraat 49PO Box 817 3000 Leuven Belgium2Department of Clinical and Chemical Pathology Inherited Metabolic Disease Laboratory Center of Social and Preventive MedicineFaculty of Medicine Cairo University 2 Ali Pasha Ibrahim Street Room 409 Monira PO Box 11628 Cairo Egypt3Department of Pediatric Nephrology Radboud University Medical Center Post 804 Postbus 9101 6500 HB Nijmegen Netherlands

Correspondence should be addressed to Mohamed A Elmonem mohamedabdelmonemkasralainyedueg

Received 30 September 2015 Accepted 16 December 2015

Academic Editor Qi-Zhuang Ye

Copyright copy 2016 Mohamed A Elmonem et alThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Chitotriosidase enzyme (EC 32114) is the major active chitinase in the human body It is produced mainly by activatedmacrophages in which its expression is regulated by multiple intrinsic and extrinsic signals Chitotriosidase was confirmedas essential element in the innate immunity against chitin containing organisms such as fungi and protozoa however itsimmunomodulatory effects extend far beyond innate immunity In the current reviewwewill try to explore the expanding spectrumof immunological roles played by chitotriosidase enzyme in human health and disease and will discuss its up-to-date clinical value

1 Introduction

Chitotriosidase enzyme (CHIT1 EC 32114) belonging tothe family of 18 glycosyl hydrolases was the first activechitinase to be discovered in human plasma [1] Its naturalsubstrate chitin is the second most abundant polysaccharidein nature after cellulose Chitin is the linear polymer ofN-acetylglucosamine and the main component of the cellwalls of fungi and protozoa egg shells of helminthes andthe exoskeletons of arthropods and insects however it iscompletely absent in mammals [2] Several protein membersof the same family were later detected in human plasma andtissues including the enzymatically active acidic mammalianchitinase (AMCase) [3] and chi-lectins those having a chitinbinding domain with no catalytic activity such as chitinase-3like-1 protein (CHI3L1 or YKL-40) chitinase-3 like-2 protein(CHI3L2 or YKL-39) and oviductal glycoprotein-1 (OVGP1)[4]

In man chitotriosidase is mainly expressed by differentlineages of activated blood and tissue macrophages [5ndash10]and to a lesser extent by polymorphonuclear leucocytes[11] The absence of its substrate chitin in the human body

and the exclusive production by immunologically activecells immediately elicited the investigation of chitotriosidaseinvolvement in the innate immunity against chitin coatedpathogens [12] Chitotriosidase was confirmed as an essentialfactor for the defense against many such organisms as Plas-modium falciparum [13] Wuchereria bancrofti [14] Candidaalbicans [15] Madurella mycetomatis [16] and Cryptococcusneoformans [17]

The role of chitotriosidase enzyme inside macrophagesis not limited to its chitinolytic activity against the engulfedchitin containing organisms or even to innate immunityIt has been implicated in the activation and polarizationcascades of macrophages as well as the indirect activationof other immune cells such as T helper cells and eosinophils[17ndash19] Recent studies are interested in its immunomod-ulatory effects through the processes of chitin recognitionantigen presentation induction of cell mediated immunityand synergistic effects with proteases and other enzymes tokill different types of pathogens and cancer cells [10 17ndash20]On the other hand chitotriosidase has been implicated in thepathogenesis of many human diseases through the improperinduction of inflammation and faulty tissue remodeling such

Hindawi Publishing CorporationEnzyme ResearchVolume 2016 Article ID 2682680 9 pageshttpdxdoiorg10115520162682680

2 Enzyme Research

CHIT1 gene

Ex 1

Ex 2

Ex 3

Ex 4

Ex 5

Ex 6

Ex 7

Ex 8

Ex 9

Ex 1

0Ex

11

Ex 1

2

Wild type Mutant

1p36

32

1p36

23

1p36

21

1p36

12 1p35

31p

351 1p

342

1p33 1p

322

1p31

3 1p31

1

1p22

2 1p21

31p

211 1p

132

1p12 1q

12

1q21

2 1q22

1q23

2 1q24

11q

243 1q

252

1q31

1 1q31

3

1q32

2 1q41

1q42

1 1q42

21q

43

Chr 1

24-bp 24-bp24-bp

No transcriptionTranscription

87-bp87-bp

DNA

RNA

3998400

3998400

3998400

3998400

3998400

5998400

5998400

5998400

5998400

5998400

Figure 1 Schematic representation of human chromosome 1 CHIT1 gene on chromosome 1q32 locus and the common 24-bp duplicationmutation at exon 10 of the CHIT1 gene

as bronchial asthma chronic obstructive pulmonary disease(COPD) nonalcoholic fatty liver disease and neurodegen-erative disorders like Alzheimerrsquos disease and amyotrophiclateral sclerosis [19 21ndash24]

In the current review we will provide a summary ofbasic information about the enzyme and we will discuss itsimmunomodulatory effects in humans over both innate andacquired immunity together with its current and possiblefuture clinical applications

2 Genetics

All the genes encoding active chitinases and chitinase-likeproteins are clustered in two loci on the human chromosome1 (1p13 and 1q32) This genetic clustering displays a highdegree of conservation among different mammals indicatingan evolutionary relationship through common ancestral geneduplication events [4]

The human chitotriosidase gene (CHIT1) extending over20 kilobases at locus 1q32 consists of 12 exons translating a466-amino acid protein [5 25] A common 24-bp duplicationmutation in exon 10 of the CHIT1 gene (Figure 1) leading toalternate splicing and in-frame deletion of 87 nucleotides (29amino acids) is responsible for almost all detected enzymedeficiencies in different populations when homozygouslymutated [25 26] Although the mutated 24-bp duplicationallele is fairly common in Caucasian individuals (4ndash6homozygous and 30ndash50 heterozygous) it is extremely rarein Sub-Saharan African individuals (0ndash2 only heterozy-gous) suggesting the evolutionary advantage of keeping thewild type enzyme in areas with high degrees of endemicparasitic and fungal disease loads [26] Interestingly the24-bp duplication mutation is much more common in theFar East in populations of Japanese Chinese and Koreanancestries as almost 30 of them are homozygous while 50are heterozygous for the mutation [27 28]

Enzyme Research 3

Other relatively common functional mutations have beenalso reported in the CHIT1 gene like G102S G354R andA442V however when homozygously mutated they are onlyassociated withmild to moderate decrease in enzyme activity[27]

3 Chemistry and Modes of Action

Chitotriosidase enzyme has twomajor forms (a 50-kilodaltonform dominant in blood stream and a 39-kilodalton formdominant in tissues) both having equal chitinolytic activitiesThe 50-kilodalton protein (466 amino acids) is initiallyproduced by macrophages containing the 39-kilodalton N-terminus having the catalytic domain and the C-terminushaving the chitin-binding domain connected together by ashort hinge region The 39-kilodalton protein (387 aminoacids) is either cleaved post-translationally in the lysosome ofmacrophages or less commonly formed through differentialRNA processing [25]

The enzyme was initially thought to be an exochitinasebecause it can hydrolyze chitotriose residues and was termedchitotriosidase based on this observation However recentstructural and binding modes studies revealed the enzyme tobe more of an endochitinase rather than an exochitinase [2930] Furthermore the strong binding affinity of chitotriosi-dase to its substrate is also responsible for the relatively hightransglycosylation activity of the enzyme even in the absenceof excess substrate concentrations making chitotriosidase acomplete independent chitinolytic machinery and this is inaccordance with its anticipated physiological role as a potentimmunological defenseweapon againstmicroorganisms con-taining chitin [31 32]

4 Stimulatory Signals

Although chitotriosidase enzyme is relatively recently linkedto human pathology many aspects of its intracellularand extracellular mechanistic actions effector and affec-tor molecules and diseases influenced by the increase ordecrease of its expression have been investigated After itsinitial association with innate immunity against chitin coatedpathogens it was rapidly identified as one of the majorprotein products of activated macrophages and hence animportant nonspecific marker of macrophage activation [12]Chitotriosidase activity was several hundred-fold elevated inthe plasma of patientswith the inflammatory based lysosomalstorage disorder Gaucherrsquos disease [1] in which macrophagesplay an essential role in the clearance of the disease sphin-golipid storagematerialThe lipid ladenmacrophage becomesthe disease histopathological pathognomonic cell in the bonemarrow and tissues or what is known as the Gaucher cellFurthermore chitotriosidase is significantly elevated in someinfections caused by bacterial and viral pathogens lacking itsnatural substrate chitin [33 34]

Several intracellular pathways have been proposed toexplain the stimulatory molecules and the activation cas-cades of chitotriosidase enzyme inside human macrophagesFigure 2 provides a simple schematic representation of amacrophage with different proposed stimulatory signals for

chitotriosidase expression as well as some of the main intra-and intercellular activities of the enzyme

Chitin naturally is a potent activator of chitotriosidaseexpression either phagocytized by themacrophage in the cellwalls of different fungi and protozoa or directly introducedto macrophages through an unidentified receptor [35 36]Chitin and its small hydrolyzed particles when coculturedwith macrophages can stimulate the production of TNF-120572and IFN-120574 [37] which can both increase the expression andactivity of chitotriosidase enzyme inside macrophages [38]Lipopolysaccharide (LPS) which is an important componentof the bacterial cell wall was also confirmed as a potentstimulant of chitotriosidase transcriptionmainly through theNF-120581B signaling pathway [38 39] which is also responsiblefor exerting the effects of TNF-120572 however IFN-120574 mostprobably produces its effect through stimulating the Jak-Stat signaling pathway [40] Another possible mechanism ofchitotriosidase activation by bacteria is through the bacterialpeptidoglycan productmuramyl dipeptide (MDP) activatingthe NOD2 signaling pathway which is also implicated inthe expression of chitotriosidase enzyme inside macrophages[41 42]

Prolactin hormone which is structurally related to manyhuman cytokines and is involved in the regulation ofmonocytemacrophage functions was also shown to increasemacrophage chitotriosidase production [43]Through study-ing signal pathway inhibitors prolactin was shown to stim-ulate chitotriosidase expression through multiple signalingpathways including the mitogen activated protein kinase(MAPK) PI3 kinase (PI3KAkt) and the protein tyrosinekinase (PTK) pathways [44]

The inflammasome system is also expected to play somerole in the activation of chitotriosidase expression as bothingested bacterial MDP and cystine crystals can stimulatemacrophages through the NLRP3 inflammasome system [4546] leading eventually to the production of IL-1120573 whicheither can stimulate the NF-120581B signaling pathway directlyor indirectly induces the production of TNF-120572 [47] thusstimulating the expression of chitotriosidase

Another efficient way to activatemacrophages and inducechitotriosidase expression is through the paracrine effectof natural killer cells (NK cells) which when exposed tocells infected with viral bacterial or fungal pathogens oreven neoplastic cells can produce large amounts of INF-120574and TNF-120572 [36 48] in the vicinity of macrophages bothincreasing the expression and release of chitotriosidase

5 Immunological Effects andClinical Perspectives

Chitotriosidase enzyme expression increases exponentiallyduring the normal monocyte to macrophage maturationprocess showing a peak of expression between the 5th dayand the 7th day of culture [18] and is recently detected to beexpressed in both macrophage polarization forms (M1 andM2) M1 macrophages or classically activated macrophagesare mainly directed to promote inflammation kill theinvading pathogens and stimulate tissue fibrosis followinginjury On the other hand M2 macrophages or alternatively

4 Enzyme Research

CHIT1 transcription

MDP

NOD2NLRP3

NF-120581B

IL-1120573NLRP3

Bacterial cell

TNF-120572Phagocytosis

Fibroblast

50-KD chito

39-KD chito

Lysosome

TGF-120573

IL-18

Fungal cell

Protozoal cell

Phagocytosis

Chitin

Chitin receptor

Stimulation of tissue fibrosis

Nucleus

Cytoplasm

LPS

IFN-120574

NF-120581BJak3

Stat1

NK cell

LPS

Prolactin

Prolactinreceptor

Macrophage

Th2 cell

Activation of acquired immunity Chitinolytic

products

Dendriticcell

Chitin

MAPKERK12

MAPK p38PI3K

Akt

PTK

Blood stream

Cancer cell

+Proteases+Other enzymes+NO

Kill

Cystine crystals

Phagocytosis

Anticancer activity

RANTESeotaxinMCP-1

LymphocyteMacrophage

Increased migratory

capacity

Eosinophil

INF-120574

TNF-120572Jak3

Stat1

Figure 2 Schematic representation of a human macrophage showing different stimuli leading to the increased expression and releaseof chitotriosidase enzyme An elaborate description of the processes implicated in increased chitotriosidase expression as well as itsimmunological effects is provided in the text 39-KD chito chitotriosidase (39 kilodalton protein) 50KD-chito chitotriosidase (50 kilodaltonprotein) ERK12 extracellular signal regulated kinases 12 IL-1120573 interleukin-1120573 IL-18 interleukin-18 INF-120574 interferon-gamma JakJanus kinase LPS lipopolysaccharide MAPK mitogen activated protein kinase MCP-1 monocyte chemotactic protein-1 MDP muramyldipeptide NF-120581B nuclear factor-kB NK cell natural killer cell NLRP3 NOD-like receptor family pyrin domain containing 3 NO nitricoxide NOD2 nucleotide-binding oligomerization domain-containing protein 2 PI3K PI3 kinase PTK protein tyrosine kinase RANTESregulated on activation normal T cell expressed and secreted Stat signal transducers and activators of transcription TGF-120573 transforminggrowth factor-beta Th2 cell T helper type 2 cell TNF-120572 tumor necrosis factor-alpha

activated macrophages provide regulatory signals to protectthe host from an exaggerated inflammatory response andpromote tissue remodeling and healing [49] The fact thatchitotriosidase is expressed almost equally in both formsdenotes its regulatory roles over processes far beyond thehydrolysis of chitin in pathogens Further studies are stillneeded to clarify the role of chitotriosidase enzyme in thealternatively activated M2 macrophages

Dendritic cells are themost important antigen presentingcells in the human body and one of the members of themonocytemacrophage lineage Although AMCase is widelyexpressed in different tissues especially in the epithelial cellsof the gastrointestinal tract and lungs [3] chitotriosidase wasthe only implicated active chitinase in the process of chitinrecognition and antigen presentation [17] Recent evidencesuggests that the induction of human T helper 2 cells (Th2)in response to pulmonary cryptococcal infection is totallydependent on chitin cleavage by chitotriosidase and thatCD11b+ conventional dendritic cells act as antigen presentingcells for the specifically fragmented chitin products [17] Fur-thermore chitotriosidase mRNA and protein concentrationswere significantly elevated in mature dendritic cells without

chitin sensitization as compared to immature dendritic cells[10] implying that chitotriosidase might be also playing arole in the process of antigen presentation regardless of thepresence of chitin

Recently activated macrophages and chitotriosidase ele-vations were implicated in the pathogenesis of nephropathiccystinosis another lysosomal storage disorder characterizedby cystine crystal accumulation inside macrophages in dif-ferent body organs Cystine crystals in vitro when incubatedwith human monocyte derived macrophages were able toactivate macrophages in a concentration dependent mannerevidenced by the increased concentrations of TNF-120572 and theconcomitant activities of chitotriosidase enzyme in culturesupernatant and in cell homogenate Furthermore plasmachitotriosidase activities in cystinotic patients correlatedpositively with leucocytes cystine concentrations makingit a potential target for the disease therapeutic monitoring[50] Cystinosis was the first crystal based disease withthe confirmed involvement of chitotriosidase enzyme in itspathogenesis making it an interesting target to investigate inother more common crystal related disorders such as goutand hyperoxaluria

Enzyme Research 5

Table 1 Human diseases associated with elevated chitotriosidase enzyme

Disease group Disease Proposed clinical value (sample type) References

Lysosomal storage diseases

Gaucher Screening therapeutic monitoring (PS) [1 62]

Niemann-Pick AB and C Screening therapeutic monitoring (PS) [65]

Cystinosis Therapeutic monitoring (PS) [50]

Fabry Therapeutic monitoring (PS) [66]

Krabbe Screening marker of severity (PS) [67]

Wolman Therapeutic monitoring (PS) [68]

Farber Screening (PS) [69]

GM1 Screening (PS) [70]

Sialidosis type II Screening (PS) [71]

Infectious diseases

Systemic fungal infectionsCandida albicans Madurellamycetomatis and Cryptococcusneoformans

Prognosis therapeutic monitoring (PS) [15ndash17]

Malaria Prognosis (PS) [13]

Filariasis Screening (PS) [14]

Tuberculosis Prognosis therapeutic monitoring (PS) [72]

Brucellosis Therapeutic monitoring (PS) [73]

Leprosy Prognosis therapeutic monitoring (PS) [74]Crimean-Congo hemorrhagicfever

Prognosis (PS) [34]

Respiratory diseasesAsthma Marker of severity (PS) [19 21]

COPD Marker of severity (PS BAL) [21 51]

Interstitial lung disease Screening marker of severity (BAL) [52 75]

Endocrinological diseases DiabetesMarker of endothelial damage (PS) [76]Marker of nephropathy progression (PS) [53]

Cardiovascular diseases

Atherosclerosis Marker of severity (PS) [77 78]

Stroke Prognosis (PS) [79]

Coronary artery disease Prognosis (PS) [80]

Erectile dysfunction Marker of severity (PS) [81]

Neurological diseases

Amyotrophic lateral sclerosis Screening marker of severity (PS CSF) [24 82]

Alzheimerrsquos disease Prognosis marker of severity (CSF) [23 83]

Cerebral adrenoleukodystrophy Prognosis (PS CSF) [84]

Neuromyelitis optica Screening (CSF) [50]

Multiple sclerosis Screening prognosis (CSF) [50]

Gynecological and obstetrical diseasesPCOS Prognosis (PS) [85]

Endometriosis Marker of severity (PS) [86]

Preeclampsia Marker of fetal compromise (UC) [87]

Miscellaneous

NAFLD Marker of severity (PS) [22]

FMF Screening marker of severity (PS) [88]

120573-Thalassemia Marker of severity therapeutic monitoring (PS) [89]

Sarcoidosis Marker of severity therapeutic monitoring (PS) [63]

Acute appendicitis Screening (PS) [90]

Juvenile idiopathic arthritis Screening marker of severity (SV) [91]

Prostate cancer Prognosis (PS) [92]BAL bronchoalveolar lavage COPD chronic obstructive pulmonary disease CSF cerebrospinal fluid FMF familialMediterranean fever GM1 gangliosidosisM1 NAFLD nonalcoholic fatty liver disease PCOS polycystic ovarian syndrome PS plasma or serum SV synovial fluid UC umbilical cord blood

6 Enzyme Research

Chitotriosidase also mediates many inflammatory pro-cesses through the direct stimulation of different inflamma-tory mediators such as IL-8 MMP9 (collagenase type IV)MCP-1 (CCL2) RANTES (CCL5) and eotaxin (CCL11) thusincreasing the migratory capacity of many immunologicalcells including T lymphocytes macrophages and eosinophils[51 52] Levels of chitotriosidase activities strongly corre-lated with the concentrations of IL-1120573 and TNF-120572 in thebronchoalveolar lavage (BAL) of COPD patients supportingthe hypothesis of a mutual regulation cascade in the pro-duction of these inflammatory mediators [52] Furthermorechitotriosidase was involved in the induction of fibrosis in themurine model of interstitial lung disease as the bleomycin-induced pulmonary fibrosis was significantly reduced in119862ℎ1198941199051minusminus mice and significantly enhanced in lungs from Chit1overexpressing transgenic mice This effect is explained bythe activation of fibroblasts through enhancing TGF-120573 andincreasing the expression of TGF-120573 receptors 1 and 2 leadingto the activation of the Smad and MAPKERK signalingpathways [53] Similar effects have been clinically observedwith other human diseases characterized by faulty tissueremodeling and abnormal healing such as nonalcoholic fattyliver disease bronchial asthma and diabetic nephropathyin which chitotriosidase plasma activities strongly correlatedwith disease progression andor the degree of tissue fibrosis[21 22 54] Targeting the chitotriosidase activation cascadethrough the administration of specific antibodies or pan-chitinase inhibitors significantly ameliorates inflammationand fibrosis in several animal models of autoimmune dis-eases most likely by suppressing the chitotriosidase depen-dent release of different cytokines and chemokines [55]however the safety of this approach in humans is not yetdetermined as it might increase the susceptibility to fungaland protozoal infections

Chitinases and chi-lectins could play a detrimental rolein human cancer development especially CHI3L1 (YKL-40)which has been associatedwith increased tumor angiogenesisand bad prognosis in many human neoplasms such as breastlung and cervical cancers [56ndash58] On the other handchitinases are also believed to have some anticancer cellactivities [59] Macrophages were always considered as aprimary defense line against neoplastic cells but the exactmechanisms beyond this action were not very clear [60]Speculations were made about a combined effect of releasedNO and H

2

O2

however there was no much evidence tosupport this hypothesis [20] Recently bacterial and humanchitinases were both confirmed as having strong synergisticeffects with protease enzymes produced by macrophagesto dissolve mucin [61] This mucolytic activity selectivelyattacked the altered mucin in the cancer cell wall of animalmodels and not the healthy cell mucin [59] It is too earlyto speculate about the therapeutic applications of this obser-vation as many explanatory mechanistic studies are neededto determine the specificity and the exact molecular andchemical targets of this process

Chitotriosidase is currently an established or a candidatescreeningmarker severitymarker andor therapeuticmonitorfor over 40 different diseases inherited and acquired Table 1

provides a summary of human diseases clinically associatedwith macrophage activation and chitotriosidase enzyme pro-duction Being a nonspecific marker of macrophage activa-tion and deficient in about 6 of normal population clearlylimits chitotriosidase usability as a screeningmarker formanydiseases however in established diagnosed nondeficientpatients chitotriosidase is an excellent marker to monitorcompliance and response to treatment [62 63] especiallywhen the treatment targets inflammatory pathways And insome diseases its marked elevations made it also a quitebeneficial screening marker as in Gaucherrsquos disease evenwhen other lysosomal storage disorders are suspected [64]

6 Conclusions

Being a sensitive biomarker of macrophage activation chi-totriosidase activity is currently more and more commonlyused in clinical practice to evaluate the status and responseto treatment of inflammatory based diseases in whichmacrophages play a significant role The interesting mixtureof harmful and beneficial immunological effectsmade humanchitinases and chitotriosidase enzyme an intriguing pointof research If proven safe in humans the development oftargeted therapies either to suppress chitotriosidase activityin autoimmune and inflammatory disorders or to specificallyenhance its targeted activity to kill cancer cells or to potentiateimmunity against certain infections will not be far in thefuture

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] C E M Hollak S van Weely M H J van Oers and J M FG Aerts ldquoMarked elevation of plasma chitotriosidase activityA novel hallmark of Gaucher diseaserdquo The Journal of ClinicalInvestigation vol 93 no 3 pp 1288ndash1292 1994

[2] R N Tharanathan and F S Kittur ldquoChitinmdashthe undisputedbiomolecule of great potentialrdquo Critical Reviews in Food Scienceand Nutrition vol 43 no 1 pp 61ndash87 2003

[3] R G Boot E F C Blommaart E Swart et al ldquoIdentification ofa novel acidic mammalian chitinase distinct from chitotriosi-daserdquo The Journal of Biological Chemistry vol 276 no 9 pp6770ndash6778 2001

[4] A P Bussink D Speijer J M F G Aerts and R G BootldquoEvolution ofmammalian chitinase(-like)members of family 18glycosyl hydrolasesrdquo Genetics vol 177 no 2 pp 959ndash970 2007

[5] R G Boot G H Renkema A Strijland A J Van Zonneveldand J M F G Aerts ldquoCloning of a cDNA encoding chitotriosi-dase a human chitinase produced bymacrophagesrdquoThe Journalof Biological Chemistry vol 270 no 44 pp 26252ndash26256 1995

[6] M A Seibold S Donnelly M Solon et al ldquoChitotriosidase isthe primary active chitinase in the human lung and is modu-lated by genotype and smoking habitrdquo Journal of Allergy andClinical Immunology vol 122 no 5 pp 944ndash950 2008

Enzyme Research 7

[7] L Malaguarnera M Di Rosa A M Zambito N dellrsquoOmbra FNicoletti and M Malaguarnera ldquoChitotriosidase gene expres-sion in Kupffer cells from patients with non-alcoholic fatty liverdiseaserdquo Gut vol 55 no 9 pp 1313ndash1320 2006

[8] R G Boot T A E vanAchterberg B E vanAken et al ldquoStronginduction of members of the chitinase family of proteinsin atherosclerosis chitotriosidase and human cartilage gp-39expressed in lesion macrophagesrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 19 no 3 pp 687ndash694 1999

[9] M Di Rosa D Tibullo M Vecchio et al ldquoDetermination ofchitinases family during osteoclastogenesisrdquo Bone vol 61 pp55ndash63 2014

[10] M Di Rosa D Tibullo D Cambria et al ldquoChitotriosidaseexpression during monocyte-derived dendritic cells differenti-ation and maturationrdquo Inflammation vol 38 no 6 pp 2082ndash2091 2015

[11] L Bouzas J C Guinarte and J C Tutor ldquoChitotriosidaseactivity in plasma and mononuclear and polymorphonuclearleukocyte populationsrdquo Journal of Clinical Laboratory Analysisvol 17 no 6 pp 271ndash275 2003

[12] M van Eijk C P A A van Roomen G H Renkema et alldquoCharacterization of human phagocyte-derived chitotriosidasea component of innate immunityrdquo International Immunologyvol 17 no 11 pp 1505ndash1512 2005

[13] R Barone J Simpore L Malaguarnera S Pignatelli and SMusumeci ldquoPlasma chitotriosidase activity in acute Plasmod-ium falciparummalariardquo Clinica Chimica Acta vol 331 no 1-2pp 79ndash85 2003

[14] E H Choi P A Zimmerman C B Foster et al ldquoGenetic poly-morphisms in molecules of innate immunity and susceptibilityto infection with Wuchereria bancrofti in South Indiardquo Genesand Immunity vol 2 no 5 pp 248ndash253 2001

[15] M Vandevenne V Campisi A Freichels et al ldquoComparativefunctional analysis of the human macrophage chitotriosidaserdquoProtein Science vol 20 no 8 pp 1451ndash1463 2011

[16] P E Verwer C CNotenboomK Eadie et al ldquoA polymorphismin the chitotriosidase gene associated with risk of mycetomadue toMadurellamycetomatismycetoma a retrospective studyrdquoPLOS Neglected Tropical Diseases vol 9 no 9 Article IDe0004061 2015

[17] D L Wiesner C A Specht C K Lee et al ldquoChitin recognitionvia chitotriosidase promotes pathologic type-2 helper T cellresponses to cryptococcal infectionrdquo PLoS Pathogens vol 11 no3 Article ID e1004701 2015

[18] M Di Rosa G Malaguarnera C De Gregorio F Drago and LMalaguarnera ldquoEvaluation of CHI3L-1 and CHIT-1 expressionin differentiated and polarized macrophagesrdquo Inflammationvol 36 no 2 pp 482ndash492 2013

[19] K W Kim J Park J H Lee et al ldquoAssociation of geneticvariation in chitotriosidase with atopy in Korean childrenrdquoAnnals of Allergy Asthma and Immunology vol 110 no 6 pp444ndash449 2013

[20] X-Q Pan ldquoThe mechanism of the anticancer function of M1macrophages and their use in the clinicrdquo Chinese Journal ofCancer vol 31 no 12 pp 557ndash563 2012

[21] A J James L E Reinius M Verhoek et al ldquoThe chitinase pro-teins YKL-40 and chitotriosidase are increased in both asthmaand COPDrdquo American Journal of Respiratory and Critical CareMedicine 2015

[22] M Di Rosa K Mangano C De Gregorio F Nicoletti andL Malaguarnera ldquoAssociation of chitotriosidase genotype with

the development of non-alcoholic fatty liver diseaserdquo Hepatol-ogy Research vol 43 no 3 pp 267ndash275 2013

[23] C Rosen C H Andersson U Andreasson et al ldquoIncreasedlevels of chitotriosidase and YKL-40 in cerebrospinal fluidfrompatients withAlzheimerrsquos diseaserdquoDementia andGeriatricCognitive Disorders Extra vol 4 no 2 pp 297ndash304 2014

[24] AM Varghese A Sharma PMishra et al ldquoChitotriosidasemdashaputative biomarker for sporadic amyotrophic lateral sclerosisrdquoClinical Proteomics vol 10 no 1 article 19 2013

[25] R G Boot G H Renkema M Verhoek et al ldquoThe humanchitotriosidase gene Nature of inherited enzyme deficiencyrdquoThe Journal of Biological Chemistry vol 273 no 40 pp 25680ndash25685 1998

[26] L Malaguarnera J Simpore D A Prodi et al ldquoA 24-bpduplication in exon 10 of human chitotriosidase gene fromthe sub-Saharan to the Mediterranean area role of parasiticdiseases and environmental conditionsrdquo Genes and Immunityvol 4 no 8 pp 570ndash574 2003

[27] P Lee JWaalen K Crain A Smargon and E Beutler ldquoHumanchitotriosidase polymorphisms G354R and A442V associatedwith reduced enzyme activityrdquo Blood Cells Molecules andDiseases vol 39 no 3 pp 353ndash360 2007

[28] KHWoo BH Lee SHHeo et al ldquoAllele frequency of a 24 bpduplication in exon 10 of the CHIT1 gene in the general Koreanpopulation and in Korean patients with Gaucher diseaserdquoJournal of Human Genetics vol 59 no 5 pp 276ndash279 2014

[29] F Fusetti H von Moeller D Houston et al ldquoStructureof human chitotriosidase Implications for specific inhibitordesign and function of mammalian chitinase-like lectinsrdquoJournal of Biological Chemistry vol 277 no 28 pp 25537ndash25544 2002

[30] K B Eide A R Lindbom V G H Eijsink A L Norberg andM Soslashrlie ldquoAnalysis of productive binding modes in the humanchitotriosidaserdquo FEBS Letters vol 587 no 21 pp 3508ndash35132013

[31] L W Stockinger K B Eide A I Dybvik et al ldquoThe effect ofthe carbohydrate binding module on substrate degradation bythe human chitotriosidaserdquo Biochimica et Biophysica Acta vol1854 no 10 pp 1494ndash1501 2015

[32] F Fadel Y Zhao R Cachau et al ldquoNew insights into theenzymatic mechanism of human chitotriosidase (CHIT1) cat-alytic domain by atomic resolution X-ray diffraction andhybrid QMMMrdquo Acta Crystallographica Section D BiologicalCrystallography vol 71 no 7 pp 1455ndash1470 2015

[33] I Labadaridis E Dimitriou M Theodorakis G Kafalidis AVelegraki and H Michelakakis ldquoChitotriosidase in neonateswith fungal and bacterial infectionsrdquo Archives of Disease inChildhood Fetal and Neonatal Edition vol 90 no 6 pp F531ndashF532 2005

[34] Y G Kurt T Cayci P Onguru et al ldquoSerum chitotriosidaseenzyme activity in patients with Crimean-Congo hemorrhagicfeverrdquo Clinical Chemistry and Laboratory Medicine vol 47 no12 pp 1543ndash1547 2009

[35] Y Shibata L A Foster W J Metzger and Q N MyrvikldquoAlveolar macrophage priming by intravenous administrationof chitin particles polymers of N-acetyl-D-glucosamine inmicerdquo Infection and Immunity vol 65 no 5 pp 1734ndash1741 1997

[36] C L Bueter C A Specht and S M Levitz ldquoInnate sensing ofchitin and chitosanrdquo PLoS Pathogens vol 9 no 1 Article IDe1003080 2013

8 Enzyme Research

[37] Y Shibata W J Metzger and Q N Myrvik ldquoChitin particle-induced cell-mediated immunity is inhibited by soluble man-nan mannose receptor-mediated phagocytosis initiates IL-12productionrdquo The Journal of Immunology vol 159 no 5 pp2462ndash2467 1997

[38] L Malaguarnera M Musumeci M Di Rosa A Scuto and SMusumeci ldquoInterferon-gamma tumor necrosis factor-120572 andlipopolysaccharide promote chitotriosidase gene expression inhuman macrophagesrdquo Journal of Clinical Laboratory Analysisvol 19 no 3 pp 128ndash132 2005

[39] O Sharif V N Bolshakov S Raines P Newham and N DPerkins ldquoTranscriptional profiling of the LPS induced NF-120581Bresponse in macrophagesrdquo BMC Immunology vol 8 article 12007

[40] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[41] J P Boyle R Parkhouse and T P Monie ldquoInsights into themolecular basis of the NOD2 signalling pathwayrdquoOpen Biologyvol 4 no 12 Article ID 140178 2014

[42] M van Eijk S S Scheij C P A A van Roomen D SpeijerR G Boot and J M F G Aerts ldquoTLR- and NOD2-dependentregulation of human phagocyte-specific chitotriosidaserdquo FEBSLetters vol 581 no 28 pp 5389ndash5395 2007

[43] L Malaguarnera M Musumeci F Licata M Di Rosa AMessina and S Musumeci ldquoProlactin induces chitotriosidasegene expression in human monocyte-derived macrophagesrdquoImmunology Letters vol 94 no 1-2 pp 57ndash63 2004

[44] M Di Rosa A M Zambito A R Marsullo G Li Volti andL Malaguarnera ldquoProlactin induces chitotriosidase expressionin human macrophages through PTK PI3-K and MAPKpathwaysrdquo Journal of Cellular Biochemistry vol 107 no 5 pp881ndash889 2009

[45] F Martinon L Agostini E Meylan and J Tschopp ldquoIden-tification of bacterial muramyl dipeptide as activator of theNALP3cryopyrin inflammasomerdquo Current Biology vol 14 no21 pp 1929ndash1934 2004

[46] G Prencipe I Caiello S Cherqui et al ldquoInflammasomeactivation by cystine crystals implications for the pathogenesisof cystinosisrdquo Journal of the American Society of Nephrology vol25 no 6 pp 1163ndash1169 2014

[47] K Lieb C Kaltschmidt B Kaltschmidt et al ldquoInterleukin-1120573uses common and distinct signaling pathways for inductionof the interleukin-6 and tumor necrosis factor 120572 genes in thehuman astrocytoma cell line U373rdquo Journal of Neurochemistryvol 66 no 4 pp 1496ndash1503 1996

[48] D Artis and H Spits ldquoThe biology of innate lymphoid cellsrdquoNature vol 517 no 7534 pp 293ndash301 2015

[49] M Di Rosa G Malaguarnera C De Gregorio F DrsquoAmico MCMazzarino and LMalaguarnera ldquoModulation of chitotriosi-dase during macrophage differentiationrdquo Cell Biochemistry andBiophysics vol 66 no 2 pp 239ndash247 2013

[50] M A Elmonem S H Makar L van den Heuvel et al ldquoClinicalutility of chitotriosidase enzyme activity in nephropathic cysti-nosisrdquoOrphanet Journal of Rare Diseases vol 9 no 1 article 1552014

[51] J Correale and M Fiol ldquoChitinase effects on immune cellresponse in neuromyelitis optica and multiple sclerosisrdquo Mul-tiple Sclerosis vol 17 no 5 pp 521ndash531 2011

[52] S Letuve A Kozhich A Humbles et al ldquoLung chitinolyticactivity and chitotriosidase are elevated in chronic obstructive

pulmonary disease and contribute to lung inflammationrdquo TheAmerican Journal of Pathology vol 176 no 2 pp 638ndash649 2010

[53] C G Lee E L Herzog F Ahangari et al ldquoChitinase 1 is abiomarker for and therapeutic target in scleroderma-associatedinterstitial lung disease that augments TGF-1205731 signalingrdquo Jour-nal of Immunology vol 189 no 5 pp 2635ndash2644 2012

[54] M A ElmonemH S Amin R A El-Essawy et al ldquoAssociationof chitotriosidase enzyme activity and genotype with the risk ofnephropathy in type 2 diabetesrdquo Clinical Biochemistry 2015

[55] T E Sutherland R M Maizels and J E Allen ldquoChitinasesand chitinase-like proteins potential therapeutic targets for thetreatment of T-helper type 2 allergiesrdquo Clinical and Experimen-tal Allergy vol 39 no 7 pp 943ndash955 2009

[56] R Shao Q J Cao R B Arenas C Bigelow B Bentley andW Yan ldquoBreast cancer expression of YKL-40 correlates withtumour grade poor differentiation and other cancer markersrdquoBritish Journal of Cancer vol 105 no 8 pp 1203ndash1209 2011

[57] X W Wang C L Cai J M Xu H Jin and Z Y Xu ldquoIncreasedexpression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesisrdquoTumor Biology vol 36 no 2 pp 901ndash907 2015

[58] N Ngernyuang R A Francescone P Jearanaikoon et alldquoChitinase 3 like 1 is associated with tumor angiogenesis incervical cancerrdquo International Journal of Biochemistry and CellBiology vol 51 no 1 pp 45ndash52 2014

[59] X Q Pan C C Shih and J Harday ldquoChitinase induces lysisof MCF-7 cells in culture and of human breast cancer xenograftB11-2 in SCIDmicerdquoAnticancer Research vol 25 no 5 pp 3167ndash3172 2005

[60] B Bonnotte N Larmonier N Favre et al ldquoIdentification oftumor-infiltratingmacrophages as the killers of tumor cells afterimmunization in a rat model systemrdquo Journal of Immunologyvol 167 no 9 pp 5077ndash5083 2001

[61] N N Sanders V G H Eijsink P S van den Pangaart etal ldquoMucolytic activity of bacterial and human chitinasesrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1770 no5 pp 839ndash846 2007

[62] E Shemesh L Deroma B Bembi et al ldquoEnzyme replacementand substrate reduction therapy for Gaucher diseaserdquo CochraneDatabase of Systematic Reviews no 3 Article ID CD0103242015

[63] M Harlander B Salobir M Zupancic M Dolensek T BavcarVodovnik andM Tercelj ldquoSerial chitotriosidasemeasurementsin sarcoidosismdashtwo to five year follow-up studyrdquo RespiratoryMedicine vol 108 no 5 pp 775ndash782 2014

[64] M A Elmonem D I Ramadan M S M Issac L A Selimand S M Elkateb ldquoBlood spot versus plasma chitotriosidase asystematic clinical comparisonrdquo Clinical Biochemistry vol 47no 1-2 pp 38ndash43 2014

[65] M Ries E Schaefer T Luhrs et al ldquoCritical assessment ofchitotriosidase analysis in the rational laboratory diagnosis ofchildren with Gaucher disease and Niemann-Pick disease typeAB and Crdquo Journal of Inherited Metabolic Disease vol 29 no5 pp 647ndash652 2006

[66] A C Vedder J Cox-Brinkman C E M Hollak et al ldquoPlasmachitotriosidase in male Fabry patients a marker for monitor-ing lipid-laden macrophages and their correction by enzymereplacement therapyrdquo Molecular Genetics and Metabolism vol89 no 3 pp 239ndash244 2006

[67] E Dimitriou M Cozar I Mavridou D Grinberg L Vilageliuand H Michelakakis ldquoThe spectrum of Krabbe disease in

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

2 Enzyme Research

CHIT1 gene

Ex 1

Ex 2

Ex 3

Ex 4

Ex 5

Ex 6

Ex 7

Ex 8

Ex 9

Ex 1

0Ex

11

Ex 1

2

Wild type Mutant

1p36

32

1p36

23

1p36

21

1p36

12 1p35

31p

351 1p

342

1p33 1p

322

1p31

3 1p31

1

1p22

2 1p21

31p

211 1p

132

1p12 1q

12

1q21

2 1q22

1q23

2 1q24

11q

243 1q

252

1q31

1 1q31

3

1q32

2 1q41

1q42

1 1q42

21q

43

Chr 1

24-bp 24-bp24-bp

No transcriptionTranscription

87-bp87-bp

DNA

RNA

3998400

3998400

3998400

3998400

3998400

5998400

5998400

5998400

5998400

5998400

Figure 1 Schematic representation of human chromosome 1 CHIT1 gene on chromosome 1q32 locus and the common 24-bp duplicationmutation at exon 10 of the CHIT1 gene

as bronchial asthma chronic obstructive pulmonary disease(COPD) nonalcoholic fatty liver disease and neurodegen-erative disorders like Alzheimerrsquos disease and amyotrophiclateral sclerosis [19 21ndash24]

In the current review we will provide a summary ofbasic information about the enzyme and we will discuss itsimmunomodulatory effects in humans over both innate andacquired immunity together with its current and possiblefuture clinical applications

2 Genetics

All the genes encoding active chitinases and chitinase-likeproteins are clustered in two loci on the human chromosome1 (1p13 and 1q32) This genetic clustering displays a highdegree of conservation among different mammals indicatingan evolutionary relationship through common ancestral geneduplication events [4]

The human chitotriosidase gene (CHIT1) extending over20 kilobases at locus 1q32 consists of 12 exons translating a466-amino acid protein [5 25] A common 24-bp duplicationmutation in exon 10 of the CHIT1 gene (Figure 1) leading toalternate splicing and in-frame deletion of 87 nucleotides (29amino acids) is responsible for almost all detected enzymedeficiencies in different populations when homozygouslymutated [25 26] Although the mutated 24-bp duplicationallele is fairly common in Caucasian individuals (4ndash6homozygous and 30ndash50 heterozygous) it is extremely rarein Sub-Saharan African individuals (0ndash2 only heterozy-gous) suggesting the evolutionary advantage of keeping thewild type enzyme in areas with high degrees of endemicparasitic and fungal disease loads [26] Interestingly the24-bp duplication mutation is much more common in theFar East in populations of Japanese Chinese and Koreanancestries as almost 30 of them are homozygous while 50are heterozygous for the mutation [27 28]

Enzyme Research 3

Other relatively common functional mutations have beenalso reported in the CHIT1 gene like G102S G354R andA442V however when homozygously mutated they are onlyassociated withmild to moderate decrease in enzyme activity[27]

3 Chemistry and Modes of Action

Chitotriosidase enzyme has twomajor forms (a 50-kilodaltonform dominant in blood stream and a 39-kilodalton formdominant in tissues) both having equal chitinolytic activitiesThe 50-kilodalton protein (466 amino acids) is initiallyproduced by macrophages containing the 39-kilodalton N-terminus having the catalytic domain and the C-terminushaving the chitin-binding domain connected together by ashort hinge region The 39-kilodalton protein (387 aminoacids) is either cleaved post-translationally in the lysosome ofmacrophages or less commonly formed through differentialRNA processing [25]

The enzyme was initially thought to be an exochitinasebecause it can hydrolyze chitotriose residues and was termedchitotriosidase based on this observation However recentstructural and binding modes studies revealed the enzyme tobe more of an endochitinase rather than an exochitinase [2930] Furthermore the strong binding affinity of chitotriosi-dase to its substrate is also responsible for the relatively hightransglycosylation activity of the enzyme even in the absenceof excess substrate concentrations making chitotriosidase acomplete independent chitinolytic machinery and this is inaccordance with its anticipated physiological role as a potentimmunological defenseweapon againstmicroorganisms con-taining chitin [31 32]

4 Stimulatory Signals

Although chitotriosidase enzyme is relatively recently linkedto human pathology many aspects of its intracellularand extracellular mechanistic actions effector and affec-tor molecules and diseases influenced by the increase ordecrease of its expression have been investigated After itsinitial association with innate immunity against chitin coatedpathogens it was rapidly identified as one of the majorprotein products of activated macrophages and hence animportant nonspecific marker of macrophage activation [12]Chitotriosidase activity was several hundred-fold elevated inthe plasma of patientswith the inflammatory based lysosomalstorage disorder Gaucherrsquos disease [1] in which macrophagesplay an essential role in the clearance of the disease sphin-golipid storagematerialThe lipid ladenmacrophage becomesthe disease histopathological pathognomonic cell in the bonemarrow and tissues or what is known as the Gaucher cellFurthermore chitotriosidase is significantly elevated in someinfections caused by bacterial and viral pathogens lacking itsnatural substrate chitin [33 34]

Several intracellular pathways have been proposed toexplain the stimulatory molecules and the activation cas-cades of chitotriosidase enzyme inside human macrophagesFigure 2 provides a simple schematic representation of amacrophage with different proposed stimulatory signals for

chitotriosidase expression as well as some of the main intra-and intercellular activities of the enzyme

Chitin naturally is a potent activator of chitotriosidaseexpression either phagocytized by themacrophage in the cellwalls of different fungi and protozoa or directly introducedto macrophages through an unidentified receptor [35 36]Chitin and its small hydrolyzed particles when coculturedwith macrophages can stimulate the production of TNF-120572and IFN-120574 [37] which can both increase the expression andactivity of chitotriosidase enzyme inside macrophages [38]Lipopolysaccharide (LPS) which is an important componentof the bacterial cell wall was also confirmed as a potentstimulant of chitotriosidase transcriptionmainly through theNF-120581B signaling pathway [38 39] which is also responsiblefor exerting the effects of TNF-120572 however IFN-120574 mostprobably produces its effect through stimulating the Jak-Stat signaling pathway [40] Another possible mechanism ofchitotriosidase activation by bacteria is through the bacterialpeptidoglycan productmuramyl dipeptide (MDP) activatingthe NOD2 signaling pathway which is also implicated inthe expression of chitotriosidase enzyme inside macrophages[41 42]

Prolactin hormone which is structurally related to manyhuman cytokines and is involved in the regulation ofmonocytemacrophage functions was also shown to increasemacrophage chitotriosidase production [43]Through study-ing signal pathway inhibitors prolactin was shown to stim-ulate chitotriosidase expression through multiple signalingpathways including the mitogen activated protein kinase(MAPK) PI3 kinase (PI3KAkt) and the protein tyrosinekinase (PTK) pathways [44]

The inflammasome system is also expected to play somerole in the activation of chitotriosidase expression as bothingested bacterial MDP and cystine crystals can stimulatemacrophages through the NLRP3 inflammasome system [4546] leading eventually to the production of IL-1120573 whicheither can stimulate the NF-120581B signaling pathway directlyor indirectly induces the production of TNF-120572 [47] thusstimulating the expression of chitotriosidase

Another efficient way to activatemacrophages and inducechitotriosidase expression is through the paracrine effectof natural killer cells (NK cells) which when exposed tocells infected with viral bacterial or fungal pathogens oreven neoplastic cells can produce large amounts of INF-120574and TNF-120572 [36 48] in the vicinity of macrophages bothincreasing the expression and release of chitotriosidase

5 Immunological Effects andClinical Perspectives

Chitotriosidase enzyme expression increases exponentiallyduring the normal monocyte to macrophage maturationprocess showing a peak of expression between the 5th dayand the 7th day of culture [18] and is recently detected to beexpressed in both macrophage polarization forms (M1 andM2) M1 macrophages or classically activated macrophagesare mainly directed to promote inflammation kill theinvading pathogens and stimulate tissue fibrosis followinginjury On the other hand M2 macrophages or alternatively

4 Enzyme Research

CHIT1 transcription

MDP

NOD2NLRP3

NF-120581B

IL-1120573NLRP3

Bacterial cell

TNF-120572Phagocytosis

Fibroblast

50-KD chito

39-KD chito

Lysosome

TGF-120573

IL-18

Fungal cell

Protozoal cell

Phagocytosis

Chitin

Chitin receptor

Stimulation of tissue fibrosis

Nucleus

Cytoplasm

LPS

IFN-120574

NF-120581BJak3

Stat1

NK cell

LPS

Prolactin

Prolactinreceptor

Macrophage

Th2 cell

Activation of acquired immunity Chitinolytic

products

Dendriticcell

Chitin

MAPKERK12

MAPK p38PI3K

Akt

PTK

Blood stream

Cancer cell

+Proteases+Other enzymes+NO

Kill

Cystine crystals

Phagocytosis

Anticancer activity

RANTESeotaxinMCP-1

LymphocyteMacrophage

Increased migratory

capacity

Eosinophil

INF-120574

TNF-120572Jak3

Stat1

Figure 2 Schematic representation of a human macrophage showing different stimuli leading to the increased expression and releaseof chitotriosidase enzyme An elaborate description of the processes implicated in increased chitotriosidase expression as well as itsimmunological effects is provided in the text 39-KD chito chitotriosidase (39 kilodalton protein) 50KD-chito chitotriosidase (50 kilodaltonprotein) ERK12 extracellular signal regulated kinases 12 IL-1120573 interleukin-1120573 IL-18 interleukin-18 INF-120574 interferon-gamma JakJanus kinase LPS lipopolysaccharide MAPK mitogen activated protein kinase MCP-1 monocyte chemotactic protein-1 MDP muramyldipeptide NF-120581B nuclear factor-kB NK cell natural killer cell NLRP3 NOD-like receptor family pyrin domain containing 3 NO nitricoxide NOD2 nucleotide-binding oligomerization domain-containing protein 2 PI3K PI3 kinase PTK protein tyrosine kinase RANTESregulated on activation normal T cell expressed and secreted Stat signal transducers and activators of transcription TGF-120573 transforminggrowth factor-beta Th2 cell T helper type 2 cell TNF-120572 tumor necrosis factor-alpha

activated macrophages provide regulatory signals to protectthe host from an exaggerated inflammatory response andpromote tissue remodeling and healing [49] The fact thatchitotriosidase is expressed almost equally in both formsdenotes its regulatory roles over processes far beyond thehydrolysis of chitin in pathogens Further studies are stillneeded to clarify the role of chitotriosidase enzyme in thealternatively activated M2 macrophages

Dendritic cells are themost important antigen presentingcells in the human body and one of the members of themonocytemacrophage lineage Although AMCase is widelyexpressed in different tissues especially in the epithelial cellsof the gastrointestinal tract and lungs [3] chitotriosidase wasthe only implicated active chitinase in the process of chitinrecognition and antigen presentation [17] Recent evidencesuggests that the induction of human T helper 2 cells (Th2)in response to pulmonary cryptococcal infection is totallydependent on chitin cleavage by chitotriosidase and thatCD11b+ conventional dendritic cells act as antigen presentingcells for the specifically fragmented chitin products [17] Fur-thermore chitotriosidase mRNA and protein concentrationswere significantly elevated in mature dendritic cells without

chitin sensitization as compared to immature dendritic cells[10] implying that chitotriosidase might be also playing arole in the process of antigen presentation regardless of thepresence of chitin

Recently activated macrophages and chitotriosidase ele-vations were implicated in the pathogenesis of nephropathiccystinosis another lysosomal storage disorder characterizedby cystine crystal accumulation inside macrophages in dif-ferent body organs Cystine crystals in vitro when incubatedwith human monocyte derived macrophages were able toactivate macrophages in a concentration dependent mannerevidenced by the increased concentrations of TNF-120572 and theconcomitant activities of chitotriosidase enzyme in culturesupernatant and in cell homogenate Furthermore plasmachitotriosidase activities in cystinotic patients correlatedpositively with leucocytes cystine concentrations makingit a potential target for the disease therapeutic monitoring[50] Cystinosis was the first crystal based disease withthe confirmed involvement of chitotriosidase enzyme in itspathogenesis making it an interesting target to investigate inother more common crystal related disorders such as goutand hyperoxaluria

Enzyme Research 5

Table 1 Human diseases associated with elevated chitotriosidase enzyme

Disease group Disease Proposed clinical value (sample type) References

Lysosomal storage diseases

Gaucher Screening therapeutic monitoring (PS) [1 62]

Niemann-Pick AB and C Screening therapeutic monitoring (PS) [65]

Cystinosis Therapeutic monitoring (PS) [50]

Fabry Therapeutic monitoring (PS) [66]

Krabbe Screening marker of severity (PS) [67]

Wolman Therapeutic monitoring (PS) [68]

Farber Screening (PS) [69]

GM1 Screening (PS) [70]

Sialidosis type II Screening (PS) [71]

Infectious diseases

Systemic fungal infectionsCandida albicans Madurellamycetomatis and Cryptococcusneoformans

Prognosis therapeutic monitoring (PS) [15ndash17]

Malaria Prognosis (PS) [13]

Filariasis Screening (PS) [14]

Tuberculosis Prognosis therapeutic monitoring (PS) [72]

Brucellosis Therapeutic monitoring (PS) [73]

Leprosy Prognosis therapeutic monitoring (PS) [74]Crimean-Congo hemorrhagicfever

Prognosis (PS) [34]

Respiratory diseasesAsthma Marker of severity (PS) [19 21]

COPD Marker of severity (PS BAL) [21 51]

Interstitial lung disease Screening marker of severity (BAL) [52 75]

Endocrinological diseases DiabetesMarker of endothelial damage (PS) [76]Marker of nephropathy progression (PS) [53]

Cardiovascular diseases

Atherosclerosis Marker of severity (PS) [77 78]

Stroke Prognosis (PS) [79]

Coronary artery disease Prognosis (PS) [80]

Erectile dysfunction Marker of severity (PS) [81]

Neurological diseases

Amyotrophic lateral sclerosis Screening marker of severity (PS CSF) [24 82]

Alzheimerrsquos disease Prognosis marker of severity (CSF) [23 83]

Cerebral adrenoleukodystrophy Prognosis (PS CSF) [84]

Neuromyelitis optica Screening (CSF) [50]

Multiple sclerosis Screening prognosis (CSF) [50]

Gynecological and obstetrical diseasesPCOS Prognosis (PS) [85]

Endometriosis Marker of severity (PS) [86]

Preeclampsia Marker of fetal compromise (UC) [87]

Miscellaneous

NAFLD Marker of severity (PS) [22]

FMF Screening marker of severity (PS) [88]

120573-Thalassemia Marker of severity therapeutic monitoring (PS) [89]

Sarcoidosis Marker of severity therapeutic monitoring (PS) [63]

Acute appendicitis Screening (PS) [90]

Juvenile idiopathic arthritis Screening marker of severity (SV) [91]

Prostate cancer Prognosis (PS) [92]BAL bronchoalveolar lavage COPD chronic obstructive pulmonary disease CSF cerebrospinal fluid FMF familialMediterranean fever GM1 gangliosidosisM1 NAFLD nonalcoholic fatty liver disease PCOS polycystic ovarian syndrome PS plasma or serum SV synovial fluid UC umbilical cord blood

6 Enzyme Research

Chitotriosidase also mediates many inflammatory pro-cesses through the direct stimulation of different inflamma-tory mediators such as IL-8 MMP9 (collagenase type IV)MCP-1 (CCL2) RANTES (CCL5) and eotaxin (CCL11) thusincreasing the migratory capacity of many immunologicalcells including T lymphocytes macrophages and eosinophils[51 52] Levels of chitotriosidase activities strongly corre-lated with the concentrations of IL-1120573 and TNF-120572 in thebronchoalveolar lavage (BAL) of COPD patients supportingthe hypothesis of a mutual regulation cascade in the pro-duction of these inflammatory mediators [52] Furthermorechitotriosidase was involved in the induction of fibrosis in themurine model of interstitial lung disease as the bleomycin-induced pulmonary fibrosis was significantly reduced in119862ℎ1198941199051minusminus mice and significantly enhanced in lungs from Chit1overexpressing transgenic mice This effect is explained bythe activation of fibroblasts through enhancing TGF-120573 andincreasing the expression of TGF-120573 receptors 1 and 2 leadingto the activation of the Smad and MAPKERK signalingpathways [53] Similar effects have been clinically observedwith other human diseases characterized by faulty tissueremodeling and abnormal healing such as nonalcoholic fattyliver disease bronchial asthma and diabetic nephropathyin which chitotriosidase plasma activities strongly correlatedwith disease progression andor the degree of tissue fibrosis[21 22 54] Targeting the chitotriosidase activation cascadethrough the administration of specific antibodies or pan-chitinase inhibitors significantly ameliorates inflammationand fibrosis in several animal models of autoimmune dis-eases most likely by suppressing the chitotriosidase depen-dent release of different cytokines and chemokines [55]however the safety of this approach in humans is not yetdetermined as it might increase the susceptibility to fungaland protozoal infections

Chitinases and chi-lectins could play a detrimental rolein human cancer development especially CHI3L1 (YKL-40)which has been associatedwith increased tumor angiogenesisand bad prognosis in many human neoplasms such as breastlung and cervical cancers [56ndash58] On the other handchitinases are also believed to have some anticancer cellactivities [59] Macrophages were always considered as aprimary defense line against neoplastic cells but the exactmechanisms beyond this action were not very clear [60]Speculations were made about a combined effect of releasedNO and H

2

O2

however there was no much evidence tosupport this hypothesis [20] Recently bacterial and humanchitinases were both confirmed as having strong synergisticeffects with protease enzymes produced by macrophagesto dissolve mucin [61] This mucolytic activity selectivelyattacked the altered mucin in the cancer cell wall of animalmodels and not the healthy cell mucin [59] It is too earlyto speculate about the therapeutic applications of this obser-vation as many explanatory mechanistic studies are neededto determine the specificity and the exact molecular andchemical targets of this process

Chitotriosidase is currently an established or a candidatescreeningmarker severitymarker andor therapeuticmonitorfor over 40 different diseases inherited and acquired Table 1

provides a summary of human diseases clinically associatedwith macrophage activation and chitotriosidase enzyme pro-duction Being a nonspecific marker of macrophage activa-tion and deficient in about 6 of normal population clearlylimits chitotriosidase usability as a screeningmarker formanydiseases however in established diagnosed nondeficientpatients chitotriosidase is an excellent marker to monitorcompliance and response to treatment [62 63] especiallywhen the treatment targets inflammatory pathways And insome diseases its marked elevations made it also a quitebeneficial screening marker as in Gaucherrsquos disease evenwhen other lysosomal storage disorders are suspected [64]

6 Conclusions

Being a sensitive biomarker of macrophage activation chi-totriosidase activity is currently more and more commonlyused in clinical practice to evaluate the status and responseto treatment of inflammatory based diseases in whichmacrophages play a significant role The interesting mixtureof harmful and beneficial immunological effectsmade humanchitinases and chitotriosidase enzyme an intriguing pointof research If proven safe in humans the development oftargeted therapies either to suppress chitotriosidase activityin autoimmune and inflammatory disorders or to specificallyenhance its targeted activity to kill cancer cells or to potentiateimmunity against certain infections will not be far in thefuture

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] C E M Hollak S van Weely M H J van Oers and J M FG Aerts ldquoMarked elevation of plasma chitotriosidase activityA novel hallmark of Gaucher diseaserdquo The Journal of ClinicalInvestigation vol 93 no 3 pp 1288ndash1292 1994

[2] R N Tharanathan and F S Kittur ldquoChitinmdashthe undisputedbiomolecule of great potentialrdquo Critical Reviews in Food Scienceand Nutrition vol 43 no 1 pp 61ndash87 2003

[3] R G Boot E F C Blommaart E Swart et al ldquoIdentification ofa novel acidic mammalian chitinase distinct from chitotriosi-daserdquo The Journal of Biological Chemistry vol 276 no 9 pp6770ndash6778 2001

[4] A P Bussink D Speijer J M F G Aerts and R G BootldquoEvolution ofmammalian chitinase(-like)members of family 18glycosyl hydrolasesrdquo Genetics vol 177 no 2 pp 959ndash970 2007

[5] R G Boot G H Renkema A Strijland A J Van Zonneveldand J M F G Aerts ldquoCloning of a cDNA encoding chitotriosi-dase a human chitinase produced bymacrophagesrdquoThe Journalof Biological Chemistry vol 270 no 44 pp 26252ndash26256 1995

[6] M A Seibold S Donnelly M Solon et al ldquoChitotriosidase isthe primary active chitinase in the human lung and is modu-lated by genotype and smoking habitrdquo Journal of Allergy andClinical Immunology vol 122 no 5 pp 944ndash950 2008

Enzyme Research 7

[7] L Malaguarnera M Di Rosa A M Zambito N dellrsquoOmbra FNicoletti and M Malaguarnera ldquoChitotriosidase gene expres-sion in Kupffer cells from patients with non-alcoholic fatty liverdiseaserdquo Gut vol 55 no 9 pp 1313ndash1320 2006

[8] R G Boot T A E vanAchterberg B E vanAken et al ldquoStronginduction of members of the chitinase family of proteinsin atherosclerosis chitotriosidase and human cartilage gp-39expressed in lesion macrophagesrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 19 no 3 pp 687ndash694 1999

[9] M Di Rosa D Tibullo M Vecchio et al ldquoDetermination ofchitinases family during osteoclastogenesisrdquo Bone vol 61 pp55ndash63 2014

[10] M Di Rosa D Tibullo D Cambria et al ldquoChitotriosidaseexpression during monocyte-derived dendritic cells differenti-ation and maturationrdquo Inflammation vol 38 no 6 pp 2082ndash2091 2015

[11] L Bouzas J C Guinarte and J C Tutor ldquoChitotriosidaseactivity in plasma and mononuclear and polymorphonuclearleukocyte populationsrdquo Journal of Clinical Laboratory Analysisvol 17 no 6 pp 271ndash275 2003

[12] M van Eijk C P A A van Roomen G H Renkema et alldquoCharacterization of human phagocyte-derived chitotriosidasea component of innate immunityrdquo International Immunologyvol 17 no 11 pp 1505ndash1512 2005

[13] R Barone J Simpore L Malaguarnera S Pignatelli and SMusumeci ldquoPlasma chitotriosidase activity in acute Plasmod-ium falciparummalariardquo Clinica Chimica Acta vol 331 no 1-2pp 79ndash85 2003

[14] E H Choi P A Zimmerman C B Foster et al ldquoGenetic poly-morphisms in molecules of innate immunity and susceptibilityto infection with Wuchereria bancrofti in South Indiardquo Genesand Immunity vol 2 no 5 pp 248ndash253 2001

[15] M Vandevenne V Campisi A Freichels et al ldquoComparativefunctional analysis of the human macrophage chitotriosidaserdquoProtein Science vol 20 no 8 pp 1451ndash1463 2011

[16] P E Verwer C CNotenboomK Eadie et al ldquoA polymorphismin the chitotriosidase gene associated with risk of mycetomadue toMadurellamycetomatismycetoma a retrospective studyrdquoPLOS Neglected Tropical Diseases vol 9 no 9 Article IDe0004061 2015

[17] D L Wiesner C A Specht C K Lee et al ldquoChitin recognitionvia chitotriosidase promotes pathologic type-2 helper T cellresponses to cryptococcal infectionrdquo PLoS Pathogens vol 11 no3 Article ID e1004701 2015

[18] M Di Rosa G Malaguarnera C De Gregorio F Drago and LMalaguarnera ldquoEvaluation of CHI3L-1 and CHIT-1 expressionin differentiated and polarized macrophagesrdquo Inflammationvol 36 no 2 pp 482ndash492 2013

[19] K W Kim J Park J H Lee et al ldquoAssociation of geneticvariation in chitotriosidase with atopy in Korean childrenrdquoAnnals of Allergy Asthma and Immunology vol 110 no 6 pp444ndash449 2013

[20] X-Q Pan ldquoThe mechanism of the anticancer function of M1macrophages and their use in the clinicrdquo Chinese Journal ofCancer vol 31 no 12 pp 557ndash563 2012

[21] A J James L E Reinius M Verhoek et al ldquoThe chitinase pro-teins YKL-40 and chitotriosidase are increased in both asthmaand COPDrdquo American Journal of Respiratory and Critical CareMedicine 2015

[22] M Di Rosa K Mangano C De Gregorio F Nicoletti andL Malaguarnera ldquoAssociation of chitotriosidase genotype with

the development of non-alcoholic fatty liver diseaserdquo Hepatol-ogy Research vol 43 no 3 pp 267ndash275 2013

[23] C Rosen C H Andersson U Andreasson et al ldquoIncreasedlevels of chitotriosidase and YKL-40 in cerebrospinal fluidfrompatients withAlzheimerrsquos diseaserdquoDementia andGeriatricCognitive Disorders Extra vol 4 no 2 pp 297ndash304 2014

[24] AM Varghese A Sharma PMishra et al ldquoChitotriosidasemdashaputative biomarker for sporadic amyotrophic lateral sclerosisrdquoClinical Proteomics vol 10 no 1 article 19 2013

[25] R G Boot G H Renkema M Verhoek et al ldquoThe humanchitotriosidase gene Nature of inherited enzyme deficiencyrdquoThe Journal of Biological Chemistry vol 273 no 40 pp 25680ndash25685 1998

[26] L Malaguarnera J Simpore D A Prodi et al ldquoA 24-bpduplication in exon 10 of human chitotriosidase gene fromthe sub-Saharan to the Mediterranean area role of parasiticdiseases and environmental conditionsrdquo Genes and Immunityvol 4 no 8 pp 570ndash574 2003

[27] P Lee JWaalen K Crain A Smargon and E Beutler ldquoHumanchitotriosidase polymorphisms G354R and A442V associatedwith reduced enzyme activityrdquo Blood Cells Molecules andDiseases vol 39 no 3 pp 353ndash360 2007

[28] KHWoo BH Lee SHHeo et al ldquoAllele frequency of a 24 bpduplication in exon 10 of the CHIT1 gene in the general Koreanpopulation and in Korean patients with Gaucher diseaserdquoJournal of Human Genetics vol 59 no 5 pp 276ndash279 2014

[29] F Fusetti H von Moeller D Houston et al ldquoStructureof human chitotriosidase Implications for specific inhibitordesign and function of mammalian chitinase-like lectinsrdquoJournal of Biological Chemistry vol 277 no 28 pp 25537ndash25544 2002

[30] K B Eide A R Lindbom V G H Eijsink A L Norberg andM Soslashrlie ldquoAnalysis of productive binding modes in the humanchitotriosidaserdquo FEBS Letters vol 587 no 21 pp 3508ndash35132013

[31] L W Stockinger K B Eide A I Dybvik et al ldquoThe effect ofthe carbohydrate binding module on substrate degradation bythe human chitotriosidaserdquo Biochimica et Biophysica Acta vol1854 no 10 pp 1494ndash1501 2015

[32] F Fadel Y Zhao R Cachau et al ldquoNew insights into theenzymatic mechanism of human chitotriosidase (CHIT1) cat-alytic domain by atomic resolution X-ray diffraction andhybrid QMMMrdquo Acta Crystallographica Section D BiologicalCrystallography vol 71 no 7 pp 1455ndash1470 2015

[33] I Labadaridis E Dimitriou M Theodorakis G Kafalidis AVelegraki and H Michelakakis ldquoChitotriosidase in neonateswith fungal and bacterial infectionsrdquo Archives of Disease inChildhood Fetal and Neonatal Edition vol 90 no 6 pp F531ndashF532 2005

[34] Y G Kurt T Cayci P Onguru et al ldquoSerum chitotriosidaseenzyme activity in patients with Crimean-Congo hemorrhagicfeverrdquo Clinical Chemistry and Laboratory Medicine vol 47 no12 pp 1543ndash1547 2009

[35] Y Shibata L A Foster W J Metzger and Q N MyrvikldquoAlveolar macrophage priming by intravenous administrationof chitin particles polymers of N-acetyl-D-glucosamine inmicerdquo Infection and Immunity vol 65 no 5 pp 1734ndash1741 1997

[36] C L Bueter C A Specht and S M Levitz ldquoInnate sensing ofchitin and chitosanrdquo PLoS Pathogens vol 9 no 1 Article IDe1003080 2013

8 Enzyme Research

[37] Y Shibata W J Metzger and Q N Myrvik ldquoChitin particle-induced cell-mediated immunity is inhibited by soluble man-nan mannose receptor-mediated phagocytosis initiates IL-12productionrdquo The Journal of Immunology vol 159 no 5 pp2462ndash2467 1997

[38] L Malaguarnera M Musumeci M Di Rosa A Scuto and SMusumeci ldquoInterferon-gamma tumor necrosis factor-120572 andlipopolysaccharide promote chitotriosidase gene expression inhuman macrophagesrdquo Journal of Clinical Laboratory Analysisvol 19 no 3 pp 128ndash132 2005

[39] O Sharif V N Bolshakov S Raines P Newham and N DPerkins ldquoTranscriptional profiling of the LPS induced NF-120581Bresponse in macrophagesrdquo BMC Immunology vol 8 article 12007

[40] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[41] J P Boyle R Parkhouse and T P Monie ldquoInsights into themolecular basis of the NOD2 signalling pathwayrdquoOpen Biologyvol 4 no 12 Article ID 140178 2014

[42] M van Eijk S S Scheij C P A A van Roomen D SpeijerR G Boot and J M F G Aerts ldquoTLR- and NOD2-dependentregulation of human phagocyte-specific chitotriosidaserdquo FEBSLetters vol 581 no 28 pp 5389ndash5395 2007

[43] L Malaguarnera M Musumeci F Licata M Di Rosa AMessina and S Musumeci ldquoProlactin induces chitotriosidasegene expression in human monocyte-derived macrophagesrdquoImmunology Letters vol 94 no 1-2 pp 57ndash63 2004

[44] M Di Rosa A M Zambito A R Marsullo G Li Volti andL Malaguarnera ldquoProlactin induces chitotriosidase expressionin human macrophages through PTK PI3-K and MAPKpathwaysrdquo Journal of Cellular Biochemistry vol 107 no 5 pp881ndash889 2009

[45] F Martinon L Agostini E Meylan and J Tschopp ldquoIden-tification of bacterial muramyl dipeptide as activator of theNALP3cryopyrin inflammasomerdquo Current Biology vol 14 no21 pp 1929ndash1934 2004

[46] G Prencipe I Caiello S Cherqui et al ldquoInflammasomeactivation by cystine crystals implications for the pathogenesisof cystinosisrdquo Journal of the American Society of Nephrology vol25 no 6 pp 1163ndash1169 2014

[47] K Lieb C Kaltschmidt B Kaltschmidt et al ldquoInterleukin-1120573uses common and distinct signaling pathways for inductionof the interleukin-6 and tumor necrosis factor 120572 genes in thehuman astrocytoma cell line U373rdquo Journal of Neurochemistryvol 66 no 4 pp 1496ndash1503 1996

[48] D Artis and H Spits ldquoThe biology of innate lymphoid cellsrdquoNature vol 517 no 7534 pp 293ndash301 2015

[49] M Di Rosa G Malaguarnera C De Gregorio F DrsquoAmico MCMazzarino and LMalaguarnera ldquoModulation of chitotriosi-dase during macrophage differentiationrdquo Cell Biochemistry andBiophysics vol 66 no 2 pp 239ndash247 2013

[50] M A Elmonem S H Makar L van den Heuvel et al ldquoClinicalutility of chitotriosidase enzyme activity in nephropathic cysti-nosisrdquoOrphanet Journal of Rare Diseases vol 9 no 1 article 1552014

[51] J Correale and M Fiol ldquoChitinase effects on immune cellresponse in neuromyelitis optica and multiple sclerosisrdquo Mul-tiple Sclerosis vol 17 no 5 pp 521ndash531 2011

[52] S Letuve A Kozhich A Humbles et al ldquoLung chitinolyticactivity and chitotriosidase are elevated in chronic obstructive

pulmonary disease and contribute to lung inflammationrdquo TheAmerican Journal of Pathology vol 176 no 2 pp 638ndash649 2010

[53] C G Lee E L Herzog F Ahangari et al ldquoChitinase 1 is abiomarker for and therapeutic target in scleroderma-associatedinterstitial lung disease that augments TGF-1205731 signalingrdquo Jour-nal of Immunology vol 189 no 5 pp 2635ndash2644 2012

[54] M A ElmonemH S Amin R A El-Essawy et al ldquoAssociationof chitotriosidase enzyme activity and genotype with the risk ofnephropathy in type 2 diabetesrdquo Clinical Biochemistry 2015

[55] T E Sutherland R M Maizels and J E Allen ldquoChitinasesand chitinase-like proteins potential therapeutic targets for thetreatment of T-helper type 2 allergiesrdquo Clinical and Experimen-tal Allergy vol 39 no 7 pp 943ndash955 2009

[56] R Shao Q J Cao R B Arenas C Bigelow B Bentley andW Yan ldquoBreast cancer expression of YKL-40 correlates withtumour grade poor differentiation and other cancer markersrdquoBritish Journal of Cancer vol 105 no 8 pp 1203ndash1209 2011

[57] X W Wang C L Cai J M Xu H Jin and Z Y Xu ldquoIncreasedexpression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesisrdquoTumor Biology vol 36 no 2 pp 901ndash907 2015

[58] N Ngernyuang R A Francescone P Jearanaikoon et alldquoChitinase 3 like 1 is associated with tumor angiogenesis incervical cancerrdquo International Journal of Biochemistry and CellBiology vol 51 no 1 pp 45ndash52 2014

[59] X Q Pan C C Shih and J Harday ldquoChitinase induces lysisof MCF-7 cells in culture and of human breast cancer xenograftB11-2 in SCIDmicerdquoAnticancer Research vol 25 no 5 pp 3167ndash3172 2005

[60] B Bonnotte N Larmonier N Favre et al ldquoIdentification oftumor-infiltratingmacrophages as the killers of tumor cells afterimmunization in a rat model systemrdquo Journal of Immunologyvol 167 no 9 pp 5077ndash5083 2001

[61] N N Sanders V G H Eijsink P S van den Pangaart etal ldquoMucolytic activity of bacterial and human chitinasesrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1770 no5 pp 839ndash846 2007

[62] E Shemesh L Deroma B Bembi et al ldquoEnzyme replacementand substrate reduction therapy for Gaucher diseaserdquo CochraneDatabase of Systematic Reviews no 3 Article ID CD0103242015

[63] M Harlander B Salobir M Zupancic M Dolensek T BavcarVodovnik andM Tercelj ldquoSerial chitotriosidasemeasurementsin sarcoidosismdashtwo to five year follow-up studyrdquo RespiratoryMedicine vol 108 no 5 pp 775ndash782 2014

[64] M A Elmonem D I Ramadan M S M Issac L A Selimand S M Elkateb ldquoBlood spot versus plasma chitotriosidase asystematic clinical comparisonrdquo Clinical Biochemistry vol 47no 1-2 pp 38ndash43 2014

[65] M Ries E Schaefer T Luhrs et al ldquoCritical assessment ofchitotriosidase analysis in the rational laboratory diagnosis ofchildren with Gaucher disease and Niemann-Pick disease typeAB and Crdquo Journal of Inherited Metabolic Disease vol 29 no5 pp 647ndash652 2006

[66] A C Vedder J Cox-Brinkman C E M Hollak et al ldquoPlasmachitotriosidase in male Fabry patients a marker for monitor-ing lipid-laden macrophages and their correction by enzymereplacement therapyrdquo Molecular Genetics and Metabolism vol89 no 3 pp 239ndash244 2006

[67] E Dimitriou M Cozar I Mavridou D Grinberg L Vilageliuand H Michelakakis ldquoThe spectrum of Krabbe disease in

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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PeptidesInternational Journal of

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International Journal of

Volume 2014

Zoology

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Enzyme Research

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International Journal of

Microbiology

Enzyme Research 3

Other relatively common functional mutations have beenalso reported in the CHIT1 gene like G102S G354R andA442V however when homozygously mutated they are onlyassociated withmild to moderate decrease in enzyme activity[27]

3 Chemistry and Modes of Action

Chitotriosidase enzyme has twomajor forms (a 50-kilodaltonform dominant in blood stream and a 39-kilodalton formdominant in tissues) both having equal chitinolytic activitiesThe 50-kilodalton protein (466 amino acids) is initiallyproduced by macrophages containing the 39-kilodalton N-terminus having the catalytic domain and the C-terminushaving the chitin-binding domain connected together by ashort hinge region The 39-kilodalton protein (387 aminoacids) is either cleaved post-translationally in the lysosome ofmacrophages or less commonly formed through differentialRNA processing [25]

The enzyme was initially thought to be an exochitinasebecause it can hydrolyze chitotriose residues and was termedchitotriosidase based on this observation However recentstructural and binding modes studies revealed the enzyme tobe more of an endochitinase rather than an exochitinase [2930] Furthermore the strong binding affinity of chitotriosi-dase to its substrate is also responsible for the relatively hightransglycosylation activity of the enzyme even in the absenceof excess substrate concentrations making chitotriosidase acomplete independent chitinolytic machinery and this is inaccordance with its anticipated physiological role as a potentimmunological defenseweapon againstmicroorganisms con-taining chitin [31 32]

4 Stimulatory Signals

Although chitotriosidase enzyme is relatively recently linkedto human pathology many aspects of its intracellularand extracellular mechanistic actions effector and affec-tor molecules and diseases influenced by the increase ordecrease of its expression have been investigated After itsinitial association with innate immunity against chitin coatedpathogens it was rapidly identified as one of the majorprotein products of activated macrophages and hence animportant nonspecific marker of macrophage activation [12]Chitotriosidase activity was several hundred-fold elevated inthe plasma of patientswith the inflammatory based lysosomalstorage disorder Gaucherrsquos disease [1] in which macrophagesplay an essential role in the clearance of the disease sphin-golipid storagematerialThe lipid ladenmacrophage becomesthe disease histopathological pathognomonic cell in the bonemarrow and tissues or what is known as the Gaucher cellFurthermore chitotriosidase is significantly elevated in someinfections caused by bacterial and viral pathogens lacking itsnatural substrate chitin [33 34]

Several intracellular pathways have been proposed toexplain the stimulatory molecules and the activation cas-cades of chitotriosidase enzyme inside human macrophagesFigure 2 provides a simple schematic representation of amacrophage with different proposed stimulatory signals for

chitotriosidase expression as well as some of the main intra-and intercellular activities of the enzyme

Chitin naturally is a potent activator of chitotriosidaseexpression either phagocytized by themacrophage in the cellwalls of different fungi and protozoa or directly introducedto macrophages through an unidentified receptor [35 36]Chitin and its small hydrolyzed particles when coculturedwith macrophages can stimulate the production of TNF-120572and IFN-120574 [37] which can both increase the expression andactivity of chitotriosidase enzyme inside macrophages [38]Lipopolysaccharide (LPS) which is an important componentof the bacterial cell wall was also confirmed as a potentstimulant of chitotriosidase transcriptionmainly through theNF-120581B signaling pathway [38 39] which is also responsiblefor exerting the effects of TNF-120572 however IFN-120574 mostprobably produces its effect through stimulating the Jak-Stat signaling pathway [40] Another possible mechanism ofchitotriosidase activation by bacteria is through the bacterialpeptidoglycan productmuramyl dipeptide (MDP) activatingthe NOD2 signaling pathway which is also implicated inthe expression of chitotriosidase enzyme inside macrophages[41 42]

Prolactin hormone which is structurally related to manyhuman cytokines and is involved in the regulation ofmonocytemacrophage functions was also shown to increasemacrophage chitotriosidase production [43]Through study-ing signal pathway inhibitors prolactin was shown to stim-ulate chitotriosidase expression through multiple signalingpathways including the mitogen activated protein kinase(MAPK) PI3 kinase (PI3KAkt) and the protein tyrosinekinase (PTK) pathways [44]

The inflammasome system is also expected to play somerole in the activation of chitotriosidase expression as bothingested bacterial MDP and cystine crystals can stimulatemacrophages through the NLRP3 inflammasome system [4546] leading eventually to the production of IL-1120573 whicheither can stimulate the NF-120581B signaling pathway directlyor indirectly induces the production of TNF-120572 [47] thusstimulating the expression of chitotriosidase

Another efficient way to activatemacrophages and inducechitotriosidase expression is through the paracrine effectof natural killer cells (NK cells) which when exposed tocells infected with viral bacterial or fungal pathogens oreven neoplastic cells can produce large amounts of INF-120574and TNF-120572 [36 48] in the vicinity of macrophages bothincreasing the expression and release of chitotriosidase

5 Immunological Effects andClinical Perspectives

Chitotriosidase enzyme expression increases exponentiallyduring the normal monocyte to macrophage maturationprocess showing a peak of expression between the 5th dayand the 7th day of culture [18] and is recently detected to beexpressed in both macrophage polarization forms (M1 andM2) M1 macrophages or classically activated macrophagesare mainly directed to promote inflammation kill theinvading pathogens and stimulate tissue fibrosis followinginjury On the other hand M2 macrophages or alternatively

4 Enzyme Research

CHIT1 transcription

MDP

NOD2NLRP3

NF-120581B

IL-1120573NLRP3

Bacterial cell

TNF-120572Phagocytosis

Fibroblast

50-KD chito

39-KD chito

Lysosome

TGF-120573

IL-18

Fungal cell

Protozoal cell

Phagocytosis

Chitin

Chitin receptor

Stimulation of tissue fibrosis

Nucleus

Cytoplasm

LPS

IFN-120574

NF-120581BJak3

Stat1

NK cell

LPS

Prolactin

Prolactinreceptor

Macrophage

Th2 cell

Activation of acquired immunity Chitinolytic

products

Dendriticcell

Chitin

MAPKERK12

MAPK p38PI3K

Akt

PTK

Blood stream

Cancer cell

+Proteases+Other enzymes+NO

Kill

Cystine crystals

Phagocytosis

Anticancer activity

RANTESeotaxinMCP-1

LymphocyteMacrophage

Increased migratory

capacity

Eosinophil

INF-120574

TNF-120572Jak3

Stat1

Figure 2 Schematic representation of a human macrophage showing different stimuli leading to the increased expression and releaseof chitotriosidase enzyme An elaborate description of the processes implicated in increased chitotriosidase expression as well as itsimmunological effects is provided in the text 39-KD chito chitotriosidase (39 kilodalton protein) 50KD-chito chitotriosidase (50 kilodaltonprotein) ERK12 extracellular signal regulated kinases 12 IL-1120573 interleukin-1120573 IL-18 interleukin-18 INF-120574 interferon-gamma JakJanus kinase LPS lipopolysaccharide MAPK mitogen activated protein kinase MCP-1 monocyte chemotactic protein-1 MDP muramyldipeptide NF-120581B nuclear factor-kB NK cell natural killer cell NLRP3 NOD-like receptor family pyrin domain containing 3 NO nitricoxide NOD2 nucleotide-binding oligomerization domain-containing protein 2 PI3K PI3 kinase PTK protein tyrosine kinase RANTESregulated on activation normal T cell expressed and secreted Stat signal transducers and activators of transcription TGF-120573 transforminggrowth factor-beta Th2 cell T helper type 2 cell TNF-120572 tumor necrosis factor-alpha

activated macrophages provide regulatory signals to protectthe host from an exaggerated inflammatory response andpromote tissue remodeling and healing [49] The fact thatchitotriosidase is expressed almost equally in both formsdenotes its regulatory roles over processes far beyond thehydrolysis of chitin in pathogens Further studies are stillneeded to clarify the role of chitotriosidase enzyme in thealternatively activated M2 macrophages

Dendritic cells are themost important antigen presentingcells in the human body and one of the members of themonocytemacrophage lineage Although AMCase is widelyexpressed in different tissues especially in the epithelial cellsof the gastrointestinal tract and lungs [3] chitotriosidase wasthe only implicated active chitinase in the process of chitinrecognition and antigen presentation [17] Recent evidencesuggests that the induction of human T helper 2 cells (Th2)in response to pulmonary cryptococcal infection is totallydependent on chitin cleavage by chitotriosidase and thatCD11b+ conventional dendritic cells act as antigen presentingcells for the specifically fragmented chitin products [17] Fur-thermore chitotriosidase mRNA and protein concentrationswere significantly elevated in mature dendritic cells without

chitin sensitization as compared to immature dendritic cells[10] implying that chitotriosidase might be also playing arole in the process of antigen presentation regardless of thepresence of chitin

Recently activated macrophages and chitotriosidase ele-vations were implicated in the pathogenesis of nephropathiccystinosis another lysosomal storage disorder characterizedby cystine crystal accumulation inside macrophages in dif-ferent body organs Cystine crystals in vitro when incubatedwith human monocyte derived macrophages were able toactivate macrophages in a concentration dependent mannerevidenced by the increased concentrations of TNF-120572 and theconcomitant activities of chitotriosidase enzyme in culturesupernatant and in cell homogenate Furthermore plasmachitotriosidase activities in cystinotic patients correlatedpositively with leucocytes cystine concentrations makingit a potential target for the disease therapeutic monitoring[50] Cystinosis was the first crystal based disease withthe confirmed involvement of chitotriosidase enzyme in itspathogenesis making it an interesting target to investigate inother more common crystal related disorders such as goutand hyperoxaluria

Enzyme Research 5

Table 1 Human diseases associated with elevated chitotriosidase enzyme

Disease group Disease Proposed clinical value (sample type) References

Lysosomal storage diseases

Gaucher Screening therapeutic monitoring (PS) [1 62]

Niemann-Pick AB and C Screening therapeutic monitoring (PS) [65]

Cystinosis Therapeutic monitoring (PS) [50]

Fabry Therapeutic monitoring (PS) [66]

Krabbe Screening marker of severity (PS) [67]

Wolman Therapeutic monitoring (PS) [68]

Farber Screening (PS) [69]

GM1 Screening (PS) [70]

Sialidosis type II Screening (PS) [71]

Infectious diseases

Systemic fungal infectionsCandida albicans Madurellamycetomatis and Cryptococcusneoformans

Prognosis therapeutic monitoring (PS) [15ndash17]

Malaria Prognosis (PS) [13]

Filariasis Screening (PS) [14]

Tuberculosis Prognosis therapeutic monitoring (PS) [72]

Brucellosis Therapeutic monitoring (PS) [73]

Leprosy Prognosis therapeutic monitoring (PS) [74]Crimean-Congo hemorrhagicfever

Prognosis (PS) [34]

Respiratory diseasesAsthma Marker of severity (PS) [19 21]

COPD Marker of severity (PS BAL) [21 51]

Interstitial lung disease Screening marker of severity (BAL) [52 75]

Endocrinological diseases DiabetesMarker of endothelial damage (PS) [76]Marker of nephropathy progression (PS) [53]

Cardiovascular diseases

Atherosclerosis Marker of severity (PS) [77 78]

Stroke Prognosis (PS) [79]

Coronary artery disease Prognosis (PS) [80]

Erectile dysfunction Marker of severity (PS) [81]

Neurological diseases

Amyotrophic lateral sclerosis Screening marker of severity (PS CSF) [24 82]

Alzheimerrsquos disease Prognosis marker of severity (CSF) [23 83]

Cerebral adrenoleukodystrophy Prognosis (PS CSF) [84]

Neuromyelitis optica Screening (CSF) [50]

Multiple sclerosis Screening prognosis (CSF) [50]

Gynecological and obstetrical diseasesPCOS Prognosis (PS) [85]

Endometriosis Marker of severity (PS) [86]

Preeclampsia Marker of fetal compromise (UC) [87]

Miscellaneous

NAFLD Marker of severity (PS) [22]

FMF Screening marker of severity (PS) [88]

120573-Thalassemia Marker of severity therapeutic monitoring (PS) [89]

Sarcoidosis Marker of severity therapeutic monitoring (PS) [63]

Acute appendicitis Screening (PS) [90]

Juvenile idiopathic arthritis Screening marker of severity (SV) [91]

Prostate cancer Prognosis (PS) [92]BAL bronchoalveolar lavage COPD chronic obstructive pulmonary disease CSF cerebrospinal fluid FMF familialMediterranean fever GM1 gangliosidosisM1 NAFLD nonalcoholic fatty liver disease PCOS polycystic ovarian syndrome PS plasma or serum SV synovial fluid UC umbilical cord blood

6 Enzyme Research

Chitotriosidase also mediates many inflammatory pro-cesses through the direct stimulation of different inflamma-tory mediators such as IL-8 MMP9 (collagenase type IV)MCP-1 (CCL2) RANTES (CCL5) and eotaxin (CCL11) thusincreasing the migratory capacity of many immunologicalcells including T lymphocytes macrophages and eosinophils[51 52] Levels of chitotriosidase activities strongly corre-lated with the concentrations of IL-1120573 and TNF-120572 in thebronchoalveolar lavage (BAL) of COPD patients supportingthe hypothesis of a mutual regulation cascade in the pro-duction of these inflammatory mediators [52] Furthermorechitotriosidase was involved in the induction of fibrosis in themurine model of interstitial lung disease as the bleomycin-induced pulmonary fibrosis was significantly reduced in119862ℎ1198941199051minusminus mice and significantly enhanced in lungs from Chit1overexpressing transgenic mice This effect is explained bythe activation of fibroblasts through enhancing TGF-120573 andincreasing the expression of TGF-120573 receptors 1 and 2 leadingto the activation of the Smad and MAPKERK signalingpathways [53] Similar effects have been clinically observedwith other human diseases characterized by faulty tissueremodeling and abnormal healing such as nonalcoholic fattyliver disease bronchial asthma and diabetic nephropathyin which chitotriosidase plasma activities strongly correlatedwith disease progression andor the degree of tissue fibrosis[21 22 54] Targeting the chitotriosidase activation cascadethrough the administration of specific antibodies or pan-chitinase inhibitors significantly ameliorates inflammationand fibrosis in several animal models of autoimmune dis-eases most likely by suppressing the chitotriosidase depen-dent release of different cytokines and chemokines [55]however the safety of this approach in humans is not yetdetermined as it might increase the susceptibility to fungaland protozoal infections

Chitinases and chi-lectins could play a detrimental rolein human cancer development especially CHI3L1 (YKL-40)which has been associatedwith increased tumor angiogenesisand bad prognosis in many human neoplasms such as breastlung and cervical cancers [56ndash58] On the other handchitinases are also believed to have some anticancer cellactivities [59] Macrophages were always considered as aprimary defense line against neoplastic cells but the exactmechanisms beyond this action were not very clear [60]Speculations were made about a combined effect of releasedNO and H

2

O2

however there was no much evidence tosupport this hypothesis [20] Recently bacterial and humanchitinases were both confirmed as having strong synergisticeffects with protease enzymes produced by macrophagesto dissolve mucin [61] This mucolytic activity selectivelyattacked the altered mucin in the cancer cell wall of animalmodels and not the healthy cell mucin [59] It is too earlyto speculate about the therapeutic applications of this obser-vation as many explanatory mechanistic studies are neededto determine the specificity and the exact molecular andchemical targets of this process

Chitotriosidase is currently an established or a candidatescreeningmarker severitymarker andor therapeuticmonitorfor over 40 different diseases inherited and acquired Table 1

provides a summary of human diseases clinically associatedwith macrophage activation and chitotriosidase enzyme pro-duction Being a nonspecific marker of macrophage activa-tion and deficient in about 6 of normal population clearlylimits chitotriosidase usability as a screeningmarker formanydiseases however in established diagnosed nondeficientpatients chitotriosidase is an excellent marker to monitorcompliance and response to treatment [62 63] especiallywhen the treatment targets inflammatory pathways And insome diseases its marked elevations made it also a quitebeneficial screening marker as in Gaucherrsquos disease evenwhen other lysosomal storage disorders are suspected [64]

6 Conclusions

Being a sensitive biomarker of macrophage activation chi-totriosidase activity is currently more and more commonlyused in clinical practice to evaluate the status and responseto treatment of inflammatory based diseases in whichmacrophages play a significant role The interesting mixtureof harmful and beneficial immunological effectsmade humanchitinases and chitotriosidase enzyme an intriguing pointof research If proven safe in humans the development oftargeted therapies either to suppress chitotriosidase activityin autoimmune and inflammatory disorders or to specificallyenhance its targeted activity to kill cancer cells or to potentiateimmunity against certain infections will not be far in thefuture

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] C E M Hollak S van Weely M H J van Oers and J M FG Aerts ldquoMarked elevation of plasma chitotriosidase activityA novel hallmark of Gaucher diseaserdquo The Journal of ClinicalInvestigation vol 93 no 3 pp 1288ndash1292 1994

[2] R N Tharanathan and F S Kittur ldquoChitinmdashthe undisputedbiomolecule of great potentialrdquo Critical Reviews in Food Scienceand Nutrition vol 43 no 1 pp 61ndash87 2003

[3] R G Boot E F C Blommaart E Swart et al ldquoIdentification ofa novel acidic mammalian chitinase distinct from chitotriosi-daserdquo The Journal of Biological Chemistry vol 276 no 9 pp6770ndash6778 2001

[4] A P Bussink D Speijer J M F G Aerts and R G BootldquoEvolution ofmammalian chitinase(-like)members of family 18glycosyl hydrolasesrdquo Genetics vol 177 no 2 pp 959ndash970 2007

[5] R G Boot G H Renkema A Strijland A J Van Zonneveldand J M F G Aerts ldquoCloning of a cDNA encoding chitotriosi-dase a human chitinase produced bymacrophagesrdquoThe Journalof Biological Chemistry vol 270 no 44 pp 26252ndash26256 1995

[6] M A Seibold S Donnelly M Solon et al ldquoChitotriosidase isthe primary active chitinase in the human lung and is modu-lated by genotype and smoking habitrdquo Journal of Allergy andClinical Immunology vol 122 no 5 pp 944ndash950 2008

Enzyme Research 7

[7] L Malaguarnera M Di Rosa A M Zambito N dellrsquoOmbra FNicoletti and M Malaguarnera ldquoChitotriosidase gene expres-sion in Kupffer cells from patients with non-alcoholic fatty liverdiseaserdquo Gut vol 55 no 9 pp 1313ndash1320 2006

[8] R G Boot T A E vanAchterberg B E vanAken et al ldquoStronginduction of members of the chitinase family of proteinsin atherosclerosis chitotriosidase and human cartilage gp-39expressed in lesion macrophagesrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 19 no 3 pp 687ndash694 1999

[9] M Di Rosa D Tibullo M Vecchio et al ldquoDetermination ofchitinases family during osteoclastogenesisrdquo Bone vol 61 pp55ndash63 2014

[10] M Di Rosa D Tibullo D Cambria et al ldquoChitotriosidaseexpression during monocyte-derived dendritic cells differenti-ation and maturationrdquo Inflammation vol 38 no 6 pp 2082ndash2091 2015

[11] L Bouzas J C Guinarte and J C Tutor ldquoChitotriosidaseactivity in plasma and mononuclear and polymorphonuclearleukocyte populationsrdquo Journal of Clinical Laboratory Analysisvol 17 no 6 pp 271ndash275 2003

[12] M van Eijk C P A A van Roomen G H Renkema et alldquoCharacterization of human phagocyte-derived chitotriosidasea component of innate immunityrdquo International Immunologyvol 17 no 11 pp 1505ndash1512 2005

[13] R Barone J Simpore L Malaguarnera S Pignatelli and SMusumeci ldquoPlasma chitotriosidase activity in acute Plasmod-ium falciparummalariardquo Clinica Chimica Acta vol 331 no 1-2pp 79ndash85 2003

[14] E H Choi P A Zimmerman C B Foster et al ldquoGenetic poly-morphisms in molecules of innate immunity and susceptibilityto infection with Wuchereria bancrofti in South Indiardquo Genesand Immunity vol 2 no 5 pp 248ndash253 2001

[15] M Vandevenne V Campisi A Freichels et al ldquoComparativefunctional analysis of the human macrophage chitotriosidaserdquoProtein Science vol 20 no 8 pp 1451ndash1463 2011

[16] P E Verwer C CNotenboomK Eadie et al ldquoA polymorphismin the chitotriosidase gene associated with risk of mycetomadue toMadurellamycetomatismycetoma a retrospective studyrdquoPLOS Neglected Tropical Diseases vol 9 no 9 Article IDe0004061 2015

[17] D L Wiesner C A Specht C K Lee et al ldquoChitin recognitionvia chitotriosidase promotes pathologic type-2 helper T cellresponses to cryptococcal infectionrdquo PLoS Pathogens vol 11 no3 Article ID e1004701 2015

[18] M Di Rosa G Malaguarnera C De Gregorio F Drago and LMalaguarnera ldquoEvaluation of CHI3L-1 and CHIT-1 expressionin differentiated and polarized macrophagesrdquo Inflammationvol 36 no 2 pp 482ndash492 2013

[19] K W Kim J Park J H Lee et al ldquoAssociation of geneticvariation in chitotriosidase with atopy in Korean childrenrdquoAnnals of Allergy Asthma and Immunology vol 110 no 6 pp444ndash449 2013

[20] X-Q Pan ldquoThe mechanism of the anticancer function of M1macrophages and their use in the clinicrdquo Chinese Journal ofCancer vol 31 no 12 pp 557ndash563 2012

[21] A J James L E Reinius M Verhoek et al ldquoThe chitinase pro-teins YKL-40 and chitotriosidase are increased in both asthmaand COPDrdquo American Journal of Respiratory and Critical CareMedicine 2015

[22] M Di Rosa K Mangano C De Gregorio F Nicoletti andL Malaguarnera ldquoAssociation of chitotriosidase genotype with

the development of non-alcoholic fatty liver diseaserdquo Hepatol-ogy Research vol 43 no 3 pp 267ndash275 2013

[23] C Rosen C H Andersson U Andreasson et al ldquoIncreasedlevels of chitotriosidase and YKL-40 in cerebrospinal fluidfrompatients withAlzheimerrsquos diseaserdquoDementia andGeriatricCognitive Disorders Extra vol 4 no 2 pp 297ndash304 2014

[24] AM Varghese A Sharma PMishra et al ldquoChitotriosidasemdashaputative biomarker for sporadic amyotrophic lateral sclerosisrdquoClinical Proteomics vol 10 no 1 article 19 2013

[25] R G Boot G H Renkema M Verhoek et al ldquoThe humanchitotriosidase gene Nature of inherited enzyme deficiencyrdquoThe Journal of Biological Chemistry vol 273 no 40 pp 25680ndash25685 1998

[26] L Malaguarnera J Simpore D A Prodi et al ldquoA 24-bpduplication in exon 10 of human chitotriosidase gene fromthe sub-Saharan to the Mediterranean area role of parasiticdiseases and environmental conditionsrdquo Genes and Immunityvol 4 no 8 pp 570ndash574 2003

[27] P Lee JWaalen K Crain A Smargon and E Beutler ldquoHumanchitotriosidase polymorphisms G354R and A442V associatedwith reduced enzyme activityrdquo Blood Cells Molecules andDiseases vol 39 no 3 pp 353ndash360 2007

[28] KHWoo BH Lee SHHeo et al ldquoAllele frequency of a 24 bpduplication in exon 10 of the CHIT1 gene in the general Koreanpopulation and in Korean patients with Gaucher diseaserdquoJournal of Human Genetics vol 59 no 5 pp 276ndash279 2014

[29] F Fusetti H von Moeller D Houston et al ldquoStructureof human chitotriosidase Implications for specific inhibitordesign and function of mammalian chitinase-like lectinsrdquoJournal of Biological Chemistry vol 277 no 28 pp 25537ndash25544 2002

[30] K B Eide A R Lindbom V G H Eijsink A L Norberg andM Soslashrlie ldquoAnalysis of productive binding modes in the humanchitotriosidaserdquo FEBS Letters vol 587 no 21 pp 3508ndash35132013

[31] L W Stockinger K B Eide A I Dybvik et al ldquoThe effect ofthe carbohydrate binding module on substrate degradation bythe human chitotriosidaserdquo Biochimica et Biophysica Acta vol1854 no 10 pp 1494ndash1501 2015

[32] F Fadel Y Zhao R Cachau et al ldquoNew insights into theenzymatic mechanism of human chitotriosidase (CHIT1) cat-alytic domain by atomic resolution X-ray diffraction andhybrid QMMMrdquo Acta Crystallographica Section D BiologicalCrystallography vol 71 no 7 pp 1455ndash1470 2015

[33] I Labadaridis E Dimitriou M Theodorakis G Kafalidis AVelegraki and H Michelakakis ldquoChitotriosidase in neonateswith fungal and bacterial infectionsrdquo Archives of Disease inChildhood Fetal and Neonatal Edition vol 90 no 6 pp F531ndashF532 2005

[34] Y G Kurt T Cayci P Onguru et al ldquoSerum chitotriosidaseenzyme activity in patients with Crimean-Congo hemorrhagicfeverrdquo Clinical Chemistry and Laboratory Medicine vol 47 no12 pp 1543ndash1547 2009

[35] Y Shibata L A Foster W J Metzger and Q N MyrvikldquoAlveolar macrophage priming by intravenous administrationof chitin particles polymers of N-acetyl-D-glucosamine inmicerdquo Infection and Immunity vol 65 no 5 pp 1734ndash1741 1997

[36] C L Bueter C A Specht and S M Levitz ldquoInnate sensing ofchitin and chitosanrdquo PLoS Pathogens vol 9 no 1 Article IDe1003080 2013

8 Enzyme Research

[37] Y Shibata W J Metzger and Q N Myrvik ldquoChitin particle-induced cell-mediated immunity is inhibited by soluble man-nan mannose receptor-mediated phagocytosis initiates IL-12productionrdquo The Journal of Immunology vol 159 no 5 pp2462ndash2467 1997

[38] L Malaguarnera M Musumeci M Di Rosa A Scuto and SMusumeci ldquoInterferon-gamma tumor necrosis factor-120572 andlipopolysaccharide promote chitotriosidase gene expression inhuman macrophagesrdquo Journal of Clinical Laboratory Analysisvol 19 no 3 pp 128ndash132 2005

[39] O Sharif V N Bolshakov S Raines P Newham and N DPerkins ldquoTranscriptional profiling of the LPS induced NF-120581Bresponse in macrophagesrdquo BMC Immunology vol 8 article 12007

[40] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[41] J P Boyle R Parkhouse and T P Monie ldquoInsights into themolecular basis of the NOD2 signalling pathwayrdquoOpen Biologyvol 4 no 12 Article ID 140178 2014

[42] M van Eijk S S Scheij C P A A van Roomen D SpeijerR G Boot and J M F G Aerts ldquoTLR- and NOD2-dependentregulation of human phagocyte-specific chitotriosidaserdquo FEBSLetters vol 581 no 28 pp 5389ndash5395 2007

[43] L Malaguarnera M Musumeci F Licata M Di Rosa AMessina and S Musumeci ldquoProlactin induces chitotriosidasegene expression in human monocyte-derived macrophagesrdquoImmunology Letters vol 94 no 1-2 pp 57ndash63 2004

[44] M Di Rosa A M Zambito A R Marsullo G Li Volti andL Malaguarnera ldquoProlactin induces chitotriosidase expressionin human macrophages through PTK PI3-K and MAPKpathwaysrdquo Journal of Cellular Biochemistry vol 107 no 5 pp881ndash889 2009

[45] F Martinon L Agostini E Meylan and J Tschopp ldquoIden-tification of bacterial muramyl dipeptide as activator of theNALP3cryopyrin inflammasomerdquo Current Biology vol 14 no21 pp 1929ndash1934 2004

[46] G Prencipe I Caiello S Cherqui et al ldquoInflammasomeactivation by cystine crystals implications for the pathogenesisof cystinosisrdquo Journal of the American Society of Nephrology vol25 no 6 pp 1163ndash1169 2014

[47] K Lieb C Kaltschmidt B Kaltschmidt et al ldquoInterleukin-1120573uses common and distinct signaling pathways for inductionof the interleukin-6 and tumor necrosis factor 120572 genes in thehuman astrocytoma cell line U373rdquo Journal of Neurochemistryvol 66 no 4 pp 1496ndash1503 1996

[48] D Artis and H Spits ldquoThe biology of innate lymphoid cellsrdquoNature vol 517 no 7534 pp 293ndash301 2015

[49] M Di Rosa G Malaguarnera C De Gregorio F DrsquoAmico MCMazzarino and LMalaguarnera ldquoModulation of chitotriosi-dase during macrophage differentiationrdquo Cell Biochemistry andBiophysics vol 66 no 2 pp 239ndash247 2013

[50] M A Elmonem S H Makar L van den Heuvel et al ldquoClinicalutility of chitotriosidase enzyme activity in nephropathic cysti-nosisrdquoOrphanet Journal of Rare Diseases vol 9 no 1 article 1552014

[51] J Correale and M Fiol ldquoChitinase effects on immune cellresponse in neuromyelitis optica and multiple sclerosisrdquo Mul-tiple Sclerosis vol 17 no 5 pp 521ndash531 2011

[52] S Letuve A Kozhich A Humbles et al ldquoLung chitinolyticactivity and chitotriosidase are elevated in chronic obstructive

pulmonary disease and contribute to lung inflammationrdquo TheAmerican Journal of Pathology vol 176 no 2 pp 638ndash649 2010

[53] C G Lee E L Herzog F Ahangari et al ldquoChitinase 1 is abiomarker for and therapeutic target in scleroderma-associatedinterstitial lung disease that augments TGF-1205731 signalingrdquo Jour-nal of Immunology vol 189 no 5 pp 2635ndash2644 2012

[54] M A ElmonemH S Amin R A El-Essawy et al ldquoAssociationof chitotriosidase enzyme activity and genotype with the risk ofnephropathy in type 2 diabetesrdquo Clinical Biochemistry 2015

[55] T E Sutherland R M Maizels and J E Allen ldquoChitinasesand chitinase-like proteins potential therapeutic targets for thetreatment of T-helper type 2 allergiesrdquo Clinical and Experimen-tal Allergy vol 39 no 7 pp 943ndash955 2009

[56] R Shao Q J Cao R B Arenas C Bigelow B Bentley andW Yan ldquoBreast cancer expression of YKL-40 correlates withtumour grade poor differentiation and other cancer markersrdquoBritish Journal of Cancer vol 105 no 8 pp 1203ndash1209 2011

[57] X W Wang C L Cai J M Xu H Jin and Z Y Xu ldquoIncreasedexpression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesisrdquoTumor Biology vol 36 no 2 pp 901ndash907 2015

[58] N Ngernyuang R A Francescone P Jearanaikoon et alldquoChitinase 3 like 1 is associated with tumor angiogenesis incervical cancerrdquo International Journal of Biochemistry and CellBiology vol 51 no 1 pp 45ndash52 2014

[59] X Q Pan C C Shih and J Harday ldquoChitinase induces lysisof MCF-7 cells in culture and of human breast cancer xenograftB11-2 in SCIDmicerdquoAnticancer Research vol 25 no 5 pp 3167ndash3172 2005

[60] B Bonnotte N Larmonier N Favre et al ldquoIdentification oftumor-infiltratingmacrophages as the killers of tumor cells afterimmunization in a rat model systemrdquo Journal of Immunologyvol 167 no 9 pp 5077ndash5083 2001

[61] N N Sanders V G H Eijsink P S van den Pangaart etal ldquoMucolytic activity of bacterial and human chitinasesrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1770 no5 pp 839ndash846 2007

[62] E Shemesh L Deroma B Bembi et al ldquoEnzyme replacementand substrate reduction therapy for Gaucher diseaserdquo CochraneDatabase of Systematic Reviews no 3 Article ID CD0103242015

[63] M Harlander B Salobir M Zupancic M Dolensek T BavcarVodovnik andM Tercelj ldquoSerial chitotriosidasemeasurementsin sarcoidosismdashtwo to five year follow-up studyrdquo RespiratoryMedicine vol 108 no 5 pp 775ndash782 2014

[64] M A Elmonem D I Ramadan M S M Issac L A Selimand S M Elkateb ldquoBlood spot versus plasma chitotriosidase asystematic clinical comparisonrdquo Clinical Biochemistry vol 47no 1-2 pp 38ndash43 2014

[65] M Ries E Schaefer T Luhrs et al ldquoCritical assessment ofchitotriosidase analysis in the rational laboratory diagnosis ofchildren with Gaucher disease and Niemann-Pick disease typeAB and Crdquo Journal of Inherited Metabolic Disease vol 29 no5 pp 647ndash652 2006

[66] A C Vedder J Cox-Brinkman C E M Hollak et al ldquoPlasmachitotriosidase in male Fabry patients a marker for monitor-ing lipid-laden macrophages and their correction by enzymereplacement therapyrdquo Molecular Genetics and Metabolism vol89 no 3 pp 239ndash244 2006

[67] E Dimitriou M Cozar I Mavridou D Grinberg L Vilageliuand H Michelakakis ldquoThe spectrum of Krabbe disease in

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

4 Enzyme Research

CHIT1 transcription

MDP

NOD2NLRP3

NF-120581B

IL-1120573NLRP3

Bacterial cell

TNF-120572Phagocytosis

Fibroblast

50-KD chito

39-KD chito

Lysosome

TGF-120573

IL-18

Fungal cell

Protozoal cell

Phagocytosis

Chitin

Chitin receptor

Stimulation of tissue fibrosis

Nucleus

Cytoplasm

LPS

IFN-120574

NF-120581BJak3

Stat1

NK cell

LPS

Prolactin

Prolactinreceptor

Macrophage

Th2 cell

Activation of acquired immunity Chitinolytic

products

Dendriticcell

Chitin

MAPKERK12

MAPK p38PI3K

Akt

PTK

Blood stream

Cancer cell

+Proteases+Other enzymes+NO

Kill

Cystine crystals

Phagocytosis

Anticancer activity

RANTESeotaxinMCP-1

LymphocyteMacrophage

Increased migratory

capacity

Eosinophil

INF-120574

TNF-120572Jak3

Stat1

Figure 2 Schematic representation of a human macrophage showing different stimuli leading to the increased expression and releaseof chitotriosidase enzyme An elaborate description of the processes implicated in increased chitotriosidase expression as well as itsimmunological effects is provided in the text 39-KD chito chitotriosidase (39 kilodalton protein) 50KD-chito chitotriosidase (50 kilodaltonprotein) ERK12 extracellular signal regulated kinases 12 IL-1120573 interleukin-1120573 IL-18 interleukin-18 INF-120574 interferon-gamma JakJanus kinase LPS lipopolysaccharide MAPK mitogen activated protein kinase MCP-1 monocyte chemotactic protein-1 MDP muramyldipeptide NF-120581B nuclear factor-kB NK cell natural killer cell NLRP3 NOD-like receptor family pyrin domain containing 3 NO nitricoxide NOD2 nucleotide-binding oligomerization domain-containing protein 2 PI3K PI3 kinase PTK protein tyrosine kinase RANTESregulated on activation normal T cell expressed and secreted Stat signal transducers and activators of transcription TGF-120573 transforminggrowth factor-beta Th2 cell T helper type 2 cell TNF-120572 tumor necrosis factor-alpha

activated macrophages provide regulatory signals to protectthe host from an exaggerated inflammatory response andpromote tissue remodeling and healing [49] The fact thatchitotriosidase is expressed almost equally in both formsdenotes its regulatory roles over processes far beyond thehydrolysis of chitin in pathogens Further studies are stillneeded to clarify the role of chitotriosidase enzyme in thealternatively activated M2 macrophages

Dendritic cells are themost important antigen presentingcells in the human body and one of the members of themonocytemacrophage lineage Although AMCase is widelyexpressed in different tissues especially in the epithelial cellsof the gastrointestinal tract and lungs [3] chitotriosidase wasthe only implicated active chitinase in the process of chitinrecognition and antigen presentation [17] Recent evidencesuggests that the induction of human T helper 2 cells (Th2)in response to pulmonary cryptococcal infection is totallydependent on chitin cleavage by chitotriosidase and thatCD11b+ conventional dendritic cells act as antigen presentingcells for the specifically fragmented chitin products [17] Fur-thermore chitotriosidase mRNA and protein concentrationswere significantly elevated in mature dendritic cells without

chitin sensitization as compared to immature dendritic cells[10] implying that chitotriosidase might be also playing arole in the process of antigen presentation regardless of thepresence of chitin

Recently activated macrophages and chitotriosidase ele-vations were implicated in the pathogenesis of nephropathiccystinosis another lysosomal storage disorder characterizedby cystine crystal accumulation inside macrophages in dif-ferent body organs Cystine crystals in vitro when incubatedwith human monocyte derived macrophages were able toactivate macrophages in a concentration dependent mannerevidenced by the increased concentrations of TNF-120572 and theconcomitant activities of chitotriosidase enzyme in culturesupernatant and in cell homogenate Furthermore plasmachitotriosidase activities in cystinotic patients correlatedpositively with leucocytes cystine concentrations makingit a potential target for the disease therapeutic monitoring[50] Cystinosis was the first crystal based disease withthe confirmed involvement of chitotriosidase enzyme in itspathogenesis making it an interesting target to investigate inother more common crystal related disorders such as goutand hyperoxaluria

Enzyme Research 5

Table 1 Human diseases associated with elevated chitotriosidase enzyme

Disease group Disease Proposed clinical value (sample type) References

Lysosomal storage diseases

Gaucher Screening therapeutic monitoring (PS) [1 62]

Niemann-Pick AB and C Screening therapeutic monitoring (PS) [65]

Cystinosis Therapeutic monitoring (PS) [50]

Fabry Therapeutic monitoring (PS) [66]

Krabbe Screening marker of severity (PS) [67]

Wolman Therapeutic monitoring (PS) [68]

Farber Screening (PS) [69]

GM1 Screening (PS) [70]

Sialidosis type II Screening (PS) [71]

Infectious diseases

Systemic fungal infectionsCandida albicans Madurellamycetomatis and Cryptococcusneoformans

Prognosis therapeutic monitoring (PS) [15ndash17]

Malaria Prognosis (PS) [13]

Filariasis Screening (PS) [14]

Tuberculosis Prognosis therapeutic monitoring (PS) [72]

Brucellosis Therapeutic monitoring (PS) [73]

Leprosy Prognosis therapeutic monitoring (PS) [74]Crimean-Congo hemorrhagicfever

Prognosis (PS) [34]

Respiratory diseasesAsthma Marker of severity (PS) [19 21]

COPD Marker of severity (PS BAL) [21 51]

Interstitial lung disease Screening marker of severity (BAL) [52 75]

Endocrinological diseases DiabetesMarker of endothelial damage (PS) [76]Marker of nephropathy progression (PS) [53]

Cardiovascular diseases

Atherosclerosis Marker of severity (PS) [77 78]

Stroke Prognosis (PS) [79]

Coronary artery disease Prognosis (PS) [80]

Erectile dysfunction Marker of severity (PS) [81]

Neurological diseases

Amyotrophic lateral sclerosis Screening marker of severity (PS CSF) [24 82]

Alzheimerrsquos disease Prognosis marker of severity (CSF) [23 83]

Cerebral adrenoleukodystrophy Prognosis (PS CSF) [84]

Neuromyelitis optica Screening (CSF) [50]

Multiple sclerosis Screening prognosis (CSF) [50]

Gynecological and obstetrical diseasesPCOS Prognosis (PS) [85]

Endometriosis Marker of severity (PS) [86]

Preeclampsia Marker of fetal compromise (UC) [87]

Miscellaneous

NAFLD Marker of severity (PS) [22]

FMF Screening marker of severity (PS) [88]

120573-Thalassemia Marker of severity therapeutic monitoring (PS) [89]

Sarcoidosis Marker of severity therapeutic monitoring (PS) [63]

Acute appendicitis Screening (PS) [90]

Juvenile idiopathic arthritis Screening marker of severity (SV) [91]

Prostate cancer Prognosis (PS) [92]BAL bronchoalveolar lavage COPD chronic obstructive pulmonary disease CSF cerebrospinal fluid FMF familialMediterranean fever GM1 gangliosidosisM1 NAFLD nonalcoholic fatty liver disease PCOS polycystic ovarian syndrome PS plasma or serum SV synovial fluid UC umbilical cord blood

6 Enzyme Research

Chitotriosidase also mediates many inflammatory pro-cesses through the direct stimulation of different inflamma-tory mediators such as IL-8 MMP9 (collagenase type IV)MCP-1 (CCL2) RANTES (CCL5) and eotaxin (CCL11) thusincreasing the migratory capacity of many immunologicalcells including T lymphocytes macrophages and eosinophils[51 52] Levels of chitotriosidase activities strongly corre-lated with the concentrations of IL-1120573 and TNF-120572 in thebronchoalveolar lavage (BAL) of COPD patients supportingthe hypothesis of a mutual regulation cascade in the pro-duction of these inflammatory mediators [52] Furthermorechitotriosidase was involved in the induction of fibrosis in themurine model of interstitial lung disease as the bleomycin-induced pulmonary fibrosis was significantly reduced in119862ℎ1198941199051minusminus mice and significantly enhanced in lungs from Chit1overexpressing transgenic mice This effect is explained bythe activation of fibroblasts through enhancing TGF-120573 andincreasing the expression of TGF-120573 receptors 1 and 2 leadingto the activation of the Smad and MAPKERK signalingpathways [53] Similar effects have been clinically observedwith other human diseases characterized by faulty tissueremodeling and abnormal healing such as nonalcoholic fattyliver disease bronchial asthma and diabetic nephropathyin which chitotriosidase plasma activities strongly correlatedwith disease progression andor the degree of tissue fibrosis[21 22 54] Targeting the chitotriosidase activation cascadethrough the administration of specific antibodies or pan-chitinase inhibitors significantly ameliorates inflammationand fibrosis in several animal models of autoimmune dis-eases most likely by suppressing the chitotriosidase depen-dent release of different cytokines and chemokines [55]however the safety of this approach in humans is not yetdetermined as it might increase the susceptibility to fungaland protozoal infections

Chitinases and chi-lectins could play a detrimental rolein human cancer development especially CHI3L1 (YKL-40)which has been associatedwith increased tumor angiogenesisand bad prognosis in many human neoplasms such as breastlung and cervical cancers [56ndash58] On the other handchitinases are also believed to have some anticancer cellactivities [59] Macrophages were always considered as aprimary defense line against neoplastic cells but the exactmechanisms beyond this action were not very clear [60]Speculations were made about a combined effect of releasedNO and H

2

O2

however there was no much evidence tosupport this hypothesis [20] Recently bacterial and humanchitinases were both confirmed as having strong synergisticeffects with protease enzymes produced by macrophagesto dissolve mucin [61] This mucolytic activity selectivelyattacked the altered mucin in the cancer cell wall of animalmodels and not the healthy cell mucin [59] It is too earlyto speculate about the therapeutic applications of this obser-vation as many explanatory mechanistic studies are neededto determine the specificity and the exact molecular andchemical targets of this process

Chitotriosidase is currently an established or a candidatescreeningmarker severitymarker andor therapeuticmonitorfor over 40 different diseases inherited and acquired Table 1

provides a summary of human diseases clinically associatedwith macrophage activation and chitotriosidase enzyme pro-duction Being a nonspecific marker of macrophage activa-tion and deficient in about 6 of normal population clearlylimits chitotriosidase usability as a screeningmarker formanydiseases however in established diagnosed nondeficientpatients chitotriosidase is an excellent marker to monitorcompliance and response to treatment [62 63] especiallywhen the treatment targets inflammatory pathways And insome diseases its marked elevations made it also a quitebeneficial screening marker as in Gaucherrsquos disease evenwhen other lysosomal storage disorders are suspected [64]

6 Conclusions

Being a sensitive biomarker of macrophage activation chi-totriosidase activity is currently more and more commonlyused in clinical practice to evaluate the status and responseto treatment of inflammatory based diseases in whichmacrophages play a significant role The interesting mixtureof harmful and beneficial immunological effectsmade humanchitinases and chitotriosidase enzyme an intriguing pointof research If proven safe in humans the development oftargeted therapies either to suppress chitotriosidase activityin autoimmune and inflammatory disorders or to specificallyenhance its targeted activity to kill cancer cells or to potentiateimmunity against certain infections will not be far in thefuture

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] C E M Hollak S van Weely M H J van Oers and J M FG Aerts ldquoMarked elevation of plasma chitotriosidase activityA novel hallmark of Gaucher diseaserdquo The Journal of ClinicalInvestigation vol 93 no 3 pp 1288ndash1292 1994

[2] R N Tharanathan and F S Kittur ldquoChitinmdashthe undisputedbiomolecule of great potentialrdquo Critical Reviews in Food Scienceand Nutrition vol 43 no 1 pp 61ndash87 2003

[3] R G Boot E F C Blommaart E Swart et al ldquoIdentification ofa novel acidic mammalian chitinase distinct from chitotriosi-daserdquo The Journal of Biological Chemistry vol 276 no 9 pp6770ndash6778 2001

[4] A P Bussink D Speijer J M F G Aerts and R G BootldquoEvolution ofmammalian chitinase(-like)members of family 18glycosyl hydrolasesrdquo Genetics vol 177 no 2 pp 959ndash970 2007

[5] R G Boot G H Renkema A Strijland A J Van Zonneveldand J M F G Aerts ldquoCloning of a cDNA encoding chitotriosi-dase a human chitinase produced bymacrophagesrdquoThe Journalof Biological Chemistry vol 270 no 44 pp 26252ndash26256 1995

[6] M A Seibold S Donnelly M Solon et al ldquoChitotriosidase isthe primary active chitinase in the human lung and is modu-lated by genotype and smoking habitrdquo Journal of Allergy andClinical Immunology vol 122 no 5 pp 944ndash950 2008

Enzyme Research 7

[7] L Malaguarnera M Di Rosa A M Zambito N dellrsquoOmbra FNicoletti and M Malaguarnera ldquoChitotriosidase gene expres-sion in Kupffer cells from patients with non-alcoholic fatty liverdiseaserdquo Gut vol 55 no 9 pp 1313ndash1320 2006

[8] R G Boot T A E vanAchterberg B E vanAken et al ldquoStronginduction of members of the chitinase family of proteinsin atherosclerosis chitotriosidase and human cartilage gp-39expressed in lesion macrophagesrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 19 no 3 pp 687ndash694 1999

[9] M Di Rosa D Tibullo M Vecchio et al ldquoDetermination ofchitinases family during osteoclastogenesisrdquo Bone vol 61 pp55ndash63 2014

[10] M Di Rosa D Tibullo D Cambria et al ldquoChitotriosidaseexpression during monocyte-derived dendritic cells differenti-ation and maturationrdquo Inflammation vol 38 no 6 pp 2082ndash2091 2015

[11] L Bouzas J C Guinarte and J C Tutor ldquoChitotriosidaseactivity in plasma and mononuclear and polymorphonuclearleukocyte populationsrdquo Journal of Clinical Laboratory Analysisvol 17 no 6 pp 271ndash275 2003

[12] M van Eijk C P A A van Roomen G H Renkema et alldquoCharacterization of human phagocyte-derived chitotriosidasea component of innate immunityrdquo International Immunologyvol 17 no 11 pp 1505ndash1512 2005

[13] R Barone J Simpore L Malaguarnera S Pignatelli and SMusumeci ldquoPlasma chitotriosidase activity in acute Plasmod-ium falciparummalariardquo Clinica Chimica Acta vol 331 no 1-2pp 79ndash85 2003

[14] E H Choi P A Zimmerman C B Foster et al ldquoGenetic poly-morphisms in molecules of innate immunity and susceptibilityto infection with Wuchereria bancrofti in South Indiardquo Genesand Immunity vol 2 no 5 pp 248ndash253 2001

[15] M Vandevenne V Campisi A Freichels et al ldquoComparativefunctional analysis of the human macrophage chitotriosidaserdquoProtein Science vol 20 no 8 pp 1451ndash1463 2011

[16] P E Verwer C CNotenboomK Eadie et al ldquoA polymorphismin the chitotriosidase gene associated with risk of mycetomadue toMadurellamycetomatismycetoma a retrospective studyrdquoPLOS Neglected Tropical Diseases vol 9 no 9 Article IDe0004061 2015

[17] D L Wiesner C A Specht C K Lee et al ldquoChitin recognitionvia chitotriosidase promotes pathologic type-2 helper T cellresponses to cryptococcal infectionrdquo PLoS Pathogens vol 11 no3 Article ID e1004701 2015

[18] M Di Rosa G Malaguarnera C De Gregorio F Drago and LMalaguarnera ldquoEvaluation of CHI3L-1 and CHIT-1 expressionin differentiated and polarized macrophagesrdquo Inflammationvol 36 no 2 pp 482ndash492 2013

[19] K W Kim J Park J H Lee et al ldquoAssociation of geneticvariation in chitotriosidase with atopy in Korean childrenrdquoAnnals of Allergy Asthma and Immunology vol 110 no 6 pp444ndash449 2013

[20] X-Q Pan ldquoThe mechanism of the anticancer function of M1macrophages and their use in the clinicrdquo Chinese Journal ofCancer vol 31 no 12 pp 557ndash563 2012

[21] A J James L E Reinius M Verhoek et al ldquoThe chitinase pro-teins YKL-40 and chitotriosidase are increased in both asthmaand COPDrdquo American Journal of Respiratory and Critical CareMedicine 2015

[22] M Di Rosa K Mangano C De Gregorio F Nicoletti andL Malaguarnera ldquoAssociation of chitotriosidase genotype with

the development of non-alcoholic fatty liver diseaserdquo Hepatol-ogy Research vol 43 no 3 pp 267ndash275 2013

[23] C Rosen C H Andersson U Andreasson et al ldquoIncreasedlevels of chitotriosidase and YKL-40 in cerebrospinal fluidfrompatients withAlzheimerrsquos diseaserdquoDementia andGeriatricCognitive Disorders Extra vol 4 no 2 pp 297ndash304 2014

[24] AM Varghese A Sharma PMishra et al ldquoChitotriosidasemdashaputative biomarker for sporadic amyotrophic lateral sclerosisrdquoClinical Proteomics vol 10 no 1 article 19 2013

[25] R G Boot G H Renkema M Verhoek et al ldquoThe humanchitotriosidase gene Nature of inherited enzyme deficiencyrdquoThe Journal of Biological Chemistry vol 273 no 40 pp 25680ndash25685 1998

[26] L Malaguarnera J Simpore D A Prodi et al ldquoA 24-bpduplication in exon 10 of human chitotriosidase gene fromthe sub-Saharan to the Mediterranean area role of parasiticdiseases and environmental conditionsrdquo Genes and Immunityvol 4 no 8 pp 570ndash574 2003

[27] P Lee JWaalen K Crain A Smargon and E Beutler ldquoHumanchitotriosidase polymorphisms G354R and A442V associatedwith reduced enzyme activityrdquo Blood Cells Molecules andDiseases vol 39 no 3 pp 353ndash360 2007

[28] KHWoo BH Lee SHHeo et al ldquoAllele frequency of a 24 bpduplication in exon 10 of the CHIT1 gene in the general Koreanpopulation and in Korean patients with Gaucher diseaserdquoJournal of Human Genetics vol 59 no 5 pp 276ndash279 2014

[29] F Fusetti H von Moeller D Houston et al ldquoStructureof human chitotriosidase Implications for specific inhibitordesign and function of mammalian chitinase-like lectinsrdquoJournal of Biological Chemistry vol 277 no 28 pp 25537ndash25544 2002

[30] K B Eide A R Lindbom V G H Eijsink A L Norberg andM Soslashrlie ldquoAnalysis of productive binding modes in the humanchitotriosidaserdquo FEBS Letters vol 587 no 21 pp 3508ndash35132013

[31] L W Stockinger K B Eide A I Dybvik et al ldquoThe effect ofthe carbohydrate binding module on substrate degradation bythe human chitotriosidaserdquo Biochimica et Biophysica Acta vol1854 no 10 pp 1494ndash1501 2015

[32] F Fadel Y Zhao R Cachau et al ldquoNew insights into theenzymatic mechanism of human chitotriosidase (CHIT1) cat-alytic domain by atomic resolution X-ray diffraction andhybrid QMMMrdquo Acta Crystallographica Section D BiologicalCrystallography vol 71 no 7 pp 1455ndash1470 2015

[33] I Labadaridis E Dimitriou M Theodorakis G Kafalidis AVelegraki and H Michelakakis ldquoChitotriosidase in neonateswith fungal and bacterial infectionsrdquo Archives of Disease inChildhood Fetal and Neonatal Edition vol 90 no 6 pp F531ndashF532 2005

[34] Y G Kurt T Cayci P Onguru et al ldquoSerum chitotriosidaseenzyme activity in patients with Crimean-Congo hemorrhagicfeverrdquo Clinical Chemistry and Laboratory Medicine vol 47 no12 pp 1543ndash1547 2009

[35] Y Shibata L A Foster W J Metzger and Q N MyrvikldquoAlveolar macrophage priming by intravenous administrationof chitin particles polymers of N-acetyl-D-glucosamine inmicerdquo Infection and Immunity vol 65 no 5 pp 1734ndash1741 1997

[36] C L Bueter C A Specht and S M Levitz ldquoInnate sensing ofchitin and chitosanrdquo PLoS Pathogens vol 9 no 1 Article IDe1003080 2013

8 Enzyme Research

[37] Y Shibata W J Metzger and Q N Myrvik ldquoChitin particle-induced cell-mediated immunity is inhibited by soluble man-nan mannose receptor-mediated phagocytosis initiates IL-12productionrdquo The Journal of Immunology vol 159 no 5 pp2462ndash2467 1997

[38] L Malaguarnera M Musumeci M Di Rosa A Scuto and SMusumeci ldquoInterferon-gamma tumor necrosis factor-120572 andlipopolysaccharide promote chitotriosidase gene expression inhuman macrophagesrdquo Journal of Clinical Laboratory Analysisvol 19 no 3 pp 128ndash132 2005

[39] O Sharif V N Bolshakov S Raines P Newham and N DPerkins ldquoTranscriptional profiling of the LPS induced NF-120581Bresponse in macrophagesrdquo BMC Immunology vol 8 article 12007

[40] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[41] J P Boyle R Parkhouse and T P Monie ldquoInsights into themolecular basis of the NOD2 signalling pathwayrdquoOpen Biologyvol 4 no 12 Article ID 140178 2014

[42] M van Eijk S S Scheij C P A A van Roomen D SpeijerR G Boot and J M F G Aerts ldquoTLR- and NOD2-dependentregulation of human phagocyte-specific chitotriosidaserdquo FEBSLetters vol 581 no 28 pp 5389ndash5395 2007

[43] L Malaguarnera M Musumeci F Licata M Di Rosa AMessina and S Musumeci ldquoProlactin induces chitotriosidasegene expression in human monocyte-derived macrophagesrdquoImmunology Letters vol 94 no 1-2 pp 57ndash63 2004

[44] M Di Rosa A M Zambito A R Marsullo G Li Volti andL Malaguarnera ldquoProlactin induces chitotriosidase expressionin human macrophages through PTK PI3-K and MAPKpathwaysrdquo Journal of Cellular Biochemistry vol 107 no 5 pp881ndash889 2009

[45] F Martinon L Agostini E Meylan and J Tschopp ldquoIden-tification of bacterial muramyl dipeptide as activator of theNALP3cryopyrin inflammasomerdquo Current Biology vol 14 no21 pp 1929ndash1934 2004

[46] G Prencipe I Caiello S Cherqui et al ldquoInflammasomeactivation by cystine crystals implications for the pathogenesisof cystinosisrdquo Journal of the American Society of Nephrology vol25 no 6 pp 1163ndash1169 2014

[47] K Lieb C Kaltschmidt B Kaltschmidt et al ldquoInterleukin-1120573uses common and distinct signaling pathways for inductionof the interleukin-6 and tumor necrosis factor 120572 genes in thehuman astrocytoma cell line U373rdquo Journal of Neurochemistryvol 66 no 4 pp 1496ndash1503 1996

[48] D Artis and H Spits ldquoThe biology of innate lymphoid cellsrdquoNature vol 517 no 7534 pp 293ndash301 2015

[49] M Di Rosa G Malaguarnera C De Gregorio F DrsquoAmico MCMazzarino and LMalaguarnera ldquoModulation of chitotriosi-dase during macrophage differentiationrdquo Cell Biochemistry andBiophysics vol 66 no 2 pp 239ndash247 2013

[50] M A Elmonem S H Makar L van den Heuvel et al ldquoClinicalutility of chitotriosidase enzyme activity in nephropathic cysti-nosisrdquoOrphanet Journal of Rare Diseases vol 9 no 1 article 1552014

[51] J Correale and M Fiol ldquoChitinase effects on immune cellresponse in neuromyelitis optica and multiple sclerosisrdquo Mul-tiple Sclerosis vol 17 no 5 pp 521ndash531 2011

[52] S Letuve A Kozhich A Humbles et al ldquoLung chitinolyticactivity and chitotriosidase are elevated in chronic obstructive

pulmonary disease and contribute to lung inflammationrdquo TheAmerican Journal of Pathology vol 176 no 2 pp 638ndash649 2010

[53] C G Lee E L Herzog F Ahangari et al ldquoChitinase 1 is abiomarker for and therapeutic target in scleroderma-associatedinterstitial lung disease that augments TGF-1205731 signalingrdquo Jour-nal of Immunology vol 189 no 5 pp 2635ndash2644 2012

[54] M A ElmonemH S Amin R A El-Essawy et al ldquoAssociationof chitotriosidase enzyme activity and genotype with the risk ofnephropathy in type 2 diabetesrdquo Clinical Biochemistry 2015

[55] T E Sutherland R M Maizels and J E Allen ldquoChitinasesand chitinase-like proteins potential therapeutic targets for thetreatment of T-helper type 2 allergiesrdquo Clinical and Experimen-tal Allergy vol 39 no 7 pp 943ndash955 2009

[56] R Shao Q J Cao R B Arenas C Bigelow B Bentley andW Yan ldquoBreast cancer expression of YKL-40 correlates withtumour grade poor differentiation and other cancer markersrdquoBritish Journal of Cancer vol 105 no 8 pp 1203ndash1209 2011

[57] X W Wang C L Cai J M Xu H Jin and Z Y Xu ldquoIncreasedexpression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesisrdquoTumor Biology vol 36 no 2 pp 901ndash907 2015

[58] N Ngernyuang R A Francescone P Jearanaikoon et alldquoChitinase 3 like 1 is associated with tumor angiogenesis incervical cancerrdquo International Journal of Biochemistry and CellBiology vol 51 no 1 pp 45ndash52 2014

[59] X Q Pan C C Shih and J Harday ldquoChitinase induces lysisof MCF-7 cells in culture and of human breast cancer xenograftB11-2 in SCIDmicerdquoAnticancer Research vol 25 no 5 pp 3167ndash3172 2005

[60] B Bonnotte N Larmonier N Favre et al ldquoIdentification oftumor-infiltratingmacrophages as the killers of tumor cells afterimmunization in a rat model systemrdquo Journal of Immunologyvol 167 no 9 pp 5077ndash5083 2001

[61] N N Sanders V G H Eijsink P S van den Pangaart etal ldquoMucolytic activity of bacterial and human chitinasesrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1770 no5 pp 839ndash846 2007

[62] E Shemesh L Deroma B Bembi et al ldquoEnzyme replacementand substrate reduction therapy for Gaucher diseaserdquo CochraneDatabase of Systematic Reviews no 3 Article ID CD0103242015

[63] M Harlander B Salobir M Zupancic M Dolensek T BavcarVodovnik andM Tercelj ldquoSerial chitotriosidasemeasurementsin sarcoidosismdashtwo to five year follow-up studyrdquo RespiratoryMedicine vol 108 no 5 pp 775ndash782 2014

[64] M A Elmonem D I Ramadan M S M Issac L A Selimand S M Elkateb ldquoBlood spot versus plasma chitotriosidase asystematic clinical comparisonrdquo Clinical Biochemistry vol 47no 1-2 pp 38ndash43 2014

[65] M Ries E Schaefer T Luhrs et al ldquoCritical assessment ofchitotriosidase analysis in the rational laboratory diagnosis ofchildren with Gaucher disease and Niemann-Pick disease typeAB and Crdquo Journal of Inherited Metabolic Disease vol 29 no5 pp 647ndash652 2006

[66] A C Vedder J Cox-Brinkman C E M Hollak et al ldquoPlasmachitotriosidase in male Fabry patients a marker for monitor-ing lipid-laden macrophages and their correction by enzymereplacement therapyrdquo Molecular Genetics and Metabolism vol89 no 3 pp 239ndash244 2006

[67] E Dimitriou M Cozar I Mavridou D Grinberg L Vilageliuand H Michelakakis ldquoThe spectrum of Krabbe disease in

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Enzyme Research 5

Table 1 Human diseases associated with elevated chitotriosidase enzyme

Disease group Disease Proposed clinical value (sample type) References

Lysosomal storage diseases

Gaucher Screening therapeutic monitoring (PS) [1 62]

Niemann-Pick AB and C Screening therapeutic monitoring (PS) [65]

Cystinosis Therapeutic monitoring (PS) [50]

Fabry Therapeutic monitoring (PS) [66]

Krabbe Screening marker of severity (PS) [67]

Wolman Therapeutic monitoring (PS) [68]

Farber Screening (PS) [69]

GM1 Screening (PS) [70]

Sialidosis type II Screening (PS) [71]

Infectious diseases

Systemic fungal infectionsCandida albicans Madurellamycetomatis and Cryptococcusneoformans

Prognosis therapeutic monitoring (PS) [15ndash17]

Malaria Prognosis (PS) [13]

Filariasis Screening (PS) [14]

Tuberculosis Prognosis therapeutic monitoring (PS) [72]

Brucellosis Therapeutic monitoring (PS) [73]

Leprosy Prognosis therapeutic monitoring (PS) [74]Crimean-Congo hemorrhagicfever

Prognosis (PS) [34]

Respiratory diseasesAsthma Marker of severity (PS) [19 21]

COPD Marker of severity (PS BAL) [21 51]

Interstitial lung disease Screening marker of severity (BAL) [52 75]

Endocrinological diseases DiabetesMarker of endothelial damage (PS) [76]Marker of nephropathy progression (PS) [53]

Cardiovascular diseases

Atherosclerosis Marker of severity (PS) [77 78]

Stroke Prognosis (PS) [79]

Coronary artery disease Prognosis (PS) [80]

Erectile dysfunction Marker of severity (PS) [81]

Neurological diseases

Amyotrophic lateral sclerosis Screening marker of severity (PS CSF) [24 82]

Alzheimerrsquos disease Prognosis marker of severity (CSF) [23 83]

Cerebral adrenoleukodystrophy Prognosis (PS CSF) [84]

Neuromyelitis optica Screening (CSF) [50]

Multiple sclerosis Screening prognosis (CSF) [50]

Gynecological and obstetrical diseasesPCOS Prognosis (PS) [85]

Endometriosis Marker of severity (PS) [86]

Preeclampsia Marker of fetal compromise (UC) [87]

Miscellaneous

NAFLD Marker of severity (PS) [22]

FMF Screening marker of severity (PS) [88]

120573-Thalassemia Marker of severity therapeutic monitoring (PS) [89]

Sarcoidosis Marker of severity therapeutic monitoring (PS) [63]

Acute appendicitis Screening (PS) [90]

Juvenile idiopathic arthritis Screening marker of severity (SV) [91]

Prostate cancer Prognosis (PS) [92]BAL bronchoalveolar lavage COPD chronic obstructive pulmonary disease CSF cerebrospinal fluid FMF familialMediterranean fever GM1 gangliosidosisM1 NAFLD nonalcoholic fatty liver disease PCOS polycystic ovarian syndrome PS plasma or serum SV synovial fluid UC umbilical cord blood

6 Enzyme Research

Chitotriosidase also mediates many inflammatory pro-cesses through the direct stimulation of different inflamma-tory mediators such as IL-8 MMP9 (collagenase type IV)MCP-1 (CCL2) RANTES (CCL5) and eotaxin (CCL11) thusincreasing the migratory capacity of many immunologicalcells including T lymphocytes macrophages and eosinophils[51 52] Levels of chitotriosidase activities strongly corre-lated with the concentrations of IL-1120573 and TNF-120572 in thebronchoalveolar lavage (BAL) of COPD patients supportingthe hypothesis of a mutual regulation cascade in the pro-duction of these inflammatory mediators [52] Furthermorechitotriosidase was involved in the induction of fibrosis in themurine model of interstitial lung disease as the bleomycin-induced pulmonary fibrosis was significantly reduced in119862ℎ1198941199051minusminus mice and significantly enhanced in lungs from Chit1overexpressing transgenic mice This effect is explained bythe activation of fibroblasts through enhancing TGF-120573 andincreasing the expression of TGF-120573 receptors 1 and 2 leadingto the activation of the Smad and MAPKERK signalingpathways [53] Similar effects have been clinically observedwith other human diseases characterized by faulty tissueremodeling and abnormal healing such as nonalcoholic fattyliver disease bronchial asthma and diabetic nephropathyin which chitotriosidase plasma activities strongly correlatedwith disease progression andor the degree of tissue fibrosis[21 22 54] Targeting the chitotriosidase activation cascadethrough the administration of specific antibodies or pan-chitinase inhibitors significantly ameliorates inflammationand fibrosis in several animal models of autoimmune dis-eases most likely by suppressing the chitotriosidase depen-dent release of different cytokines and chemokines [55]however the safety of this approach in humans is not yetdetermined as it might increase the susceptibility to fungaland protozoal infections

Chitinases and chi-lectins could play a detrimental rolein human cancer development especially CHI3L1 (YKL-40)which has been associatedwith increased tumor angiogenesisand bad prognosis in many human neoplasms such as breastlung and cervical cancers [56ndash58] On the other handchitinases are also believed to have some anticancer cellactivities [59] Macrophages were always considered as aprimary defense line against neoplastic cells but the exactmechanisms beyond this action were not very clear [60]Speculations were made about a combined effect of releasedNO and H

2

O2

however there was no much evidence tosupport this hypothesis [20] Recently bacterial and humanchitinases were both confirmed as having strong synergisticeffects with protease enzymes produced by macrophagesto dissolve mucin [61] This mucolytic activity selectivelyattacked the altered mucin in the cancer cell wall of animalmodels and not the healthy cell mucin [59] It is too earlyto speculate about the therapeutic applications of this obser-vation as many explanatory mechanistic studies are neededto determine the specificity and the exact molecular andchemical targets of this process

Chitotriosidase is currently an established or a candidatescreeningmarker severitymarker andor therapeuticmonitorfor over 40 different diseases inherited and acquired Table 1

provides a summary of human diseases clinically associatedwith macrophage activation and chitotriosidase enzyme pro-duction Being a nonspecific marker of macrophage activa-tion and deficient in about 6 of normal population clearlylimits chitotriosidase usability as a screeningmarker formanydiseases however in established diagnosed nondeficientpatients chitotriosidase is an excellent marker to monitorcompliance and response to treatment [62 63] especiallywhen the treatment targets inflammatory pathways And insome diseases its marked elevations made it also a quitebeneficial screening marker as in Gaucherrsquos disease evenwhen other lysosomal storage disorders are suspected [64]

6 Conclusions

Being a sensitive biomarker of macrophage activation chi-totriosidase activity is currently more and more commonlyused in clinical practice to evaluate the status and responseto treatment of inflammatory based diseases in whichmacrophages play a significant role The interesting mixtureof harmful and beneficial immunological effectsmade humanchitinases and chitotriosidase enzyme an intriguing pointof research If proven safe in humans the development oftargeted therapies either to suppress chitotriosidase activityin autoimmune and inflammatory disorders or to specificallyenhance its targeted activity to kill cancer cells or to potentiateimmunity against certain infections will not be far in thefuture

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] C E M Hollak S van Weely M H J van Oers and J M FG Aerts ldquoMarked elevation of plasma chitotriosidase activityA novel hallmark of Gaucher diseaserdquo The Journal of ClinicalInvestigation vol 93 no 3 pp 1288ndash1292 1994

[2] R N Tharanathan and F S Kittur ldquoChitinmdashthe undisputedbiomolecule of great potentialrdquo Critical Reviews in Food Scienceand Nutrition vol 43 no 1 pp 61ndash87 2003

[3] R G Boot E F C Blommaart E Swart et al ldquoIdentification ofa novel acidic mammalian chitinase distinct from chitotriosi-daserdquo The Journal of Biological Chemistry vol 276 no 9 pp6770ndash6778 2001

[4] A P Bussink D Speijer J M F G Aerts and R G BootldquoEvolution ofmammalian chitinase(-like)members of family 18glycosyl hydrolasesrdquo Genetics vol 177 no 2 pp 959ndash970 2007

[5] R G Boot G H Renkema A Strijland A J Van Zonneveldand J M F G Aerts ldquoCloning of a cDNA encoding chitotriosi-dase a human chitinase produced bymacrophagesrdquoThe Journalof Biological Chemistry vol 270 no 44 pp 26252ndash26256 1995

[6] M A Seibold S Donnelly M Solon et al ldquoChitotriosidase isthe primary active chitinase in the human lung and is modu-lated by genotype and smoking habitrdquo Journal of Allergy andClinical Immunology vol 122 no 5 pp 944ndash950 2008

Enzyme Research 7

[7] L Malaguarnera M Di Rosa A M Zambito N dellrsquoOmbra FNicoletti and M Malaguarnera ldquoChitotriosidase gene expres-sion in Kupffer cells from patients with non-alcoholic fatty liverdiseaserdquo Gut vol 55 no 9 pp 1313ndash1320 2006

[8] R G Boot T A E vanAchterberg B E vanAken et al ldquoStronginduction of members of the chitinase family of proteinsin atherosclerosis chitotriosidase and human cartilage gp-39expressed in lesion macrophagesrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 19 no 3 pp 687ndash694 1999

[9] M Di Rosa D Tibullo M Vecchio et al ldquoDetermination ofchitinases family during osteoclastogenesisrdquo Bone vol 61 pp55ndash63 2014

[10] M Di Rosa D Tibullo D Cambria et al ldquoChitotriosidaseexpression during monocyte-derived dendritic cells differenti-ation and maturationrdquo Inflammation vol 38 no 6 pp 2082ndash2091 2015

[11] L Bouzas J C Guinarte and J C Tutor ldquoChitotriosidaseactivity in plasma and mononuclear and polymorphonuclearleukocyte populationsrdquo Journal of Clinical Laboratory Analysisvol 17 no 6 pp 271ndash275 2003

[12] M van Eijk C P A A van Roomen G H Renkema et alldquoCharacterization of human phagocyte-derived chitotriosidasea component of innate immunityrdquo International Immunologyvol 17 no 11 pp 1505ndash1512 2005

[13] R Barone J Simpore L Malaguarnera S Pignatelli and SMusumeci ldquoPlasma chitotriosidase activity in acute Plasmod-ium falciparummalariardquo Clinica Chimica Acta vol 331 no 1-2pp 79ndash85 2003

[14] E H Choi P A Zimmerman C B Foster et al ldquoGenetic poly-morphisms in molecules of innate immunity and susceptibilityto infection with Wuchereria bancrofti in South Indiardquo Genesand Immunity vol 2 no 5 pp 248ndash253 2001

[15] M Vandevenne V Campisi A Freichels et al ldquoComparativefunctional analysis of the human macrophage chitotriosidaserdquoProtein Science vol 20 no 8 pp 1451ndash1463 2011

[16] P E Verwer C CNotenboomK Eadie et al ldquoA polymorphismin the chitotriosidase gene associated with risk of mycetomadue toMadurellamycetomatismycetoma a retrospective studyrdquoPLOS Neglected Tropical Diseases vol 9 no 9 Article IDe0004061 2015

[17] D L Wiesner C A Specht C K Lee et al ldquoChitin recognitionvia chitotriosidase promotes pathologic type-2 helper T cellresponses to cryptococcal infectionrdquo PLoS Pathogens vol 11 no3 Article ID e1004701 2015

[18] M Di Rosa G Malaguarnera C De Gregorio F Drago and LMalaguarnera ldquoEvaluation of CHI3L-1 and CHIT-1 expressionin differentiated and polarized macrophagesrdquo Inflammationvol 36 no 2 pp 482ndash492 2013

[19] K W Kim J Park J H Lee et al ldquoAssociation of geneticvariation in chitotriosidase with atopy in Korean childrenrdquoAnnals of Allergy Asthma and Immunology vol 110 no 6 pp444ndash449 2013

[20] X-Q Pan ldquoThe mechanism of the anticancer function of M1macrophages and their use in the clinicrdquo Chinese Journal ofCancer vol 31 no 12 pp 557ndash563 2012

[21] A J James L E Reinius M Verhoek et al ldquoThe chitinase pro-teins YKL-40 and chitotriosidase are increased in both asthmaand COPDrdquo American Journal of Respiratory and Critical CareMedicine 2015

[22] M Di Rosa K Mangano C De Gregorio F Nicoletti andL Malaguarnera ldquoAssociation of chitotriosidase genotype with

the development of non-alcoholic fatty liver diseaserdquo Hepatol-ogy Research vol 43 no 3 pp 267ndash275 2013

[23] C Rosen C H Andersson U Andreasson et al ldquoIncreasedlevels of chitotriosidase and YKL-40 in cerebrospinal fluidfrompatients withAlzheimerrsquos diseaserdquoDementia andGeriatricCognitive Disorders Extra vol 4 no 2 pp 297ndash304 2014

[24] AM Varghese A Sharma PMishra et al ldquoChitotriosidasemdashaputative biomarker for sporadic amyotrophic lateral sclerosisrdquoClinical Proteomics vol 10 no 1 article 19 2013

[25] R G Boot G H Renkema M Verhoek et al ldquoThe humanchitotriosidase gene Nature of inherited enzyme deficiencyrdquoThe Journal of Biological Chemistry vol 273 no 40 pp 25680ndash25685 1998

[26] L Malaguarnera J Simpore D A Prodi et al ldquoA 24-bpduplication in exon 10 of human chitotriosidase gene fromthe sub-Saharan to the Mediterranean area role of parasiticdiseases and environmental conditionsrdquo Genes and Immunityvol 4 no 8 pp 570ndash574 2003

[27] P Lee JWaalen K Crain A Smargon and E Beutler ldquoHumanchitotriosidase polymorphisms G354R and A442V associatedwith reduced enzyme activityrdquo Blood Cells Molecules andDiseases vol 39 no 3 pp 353ndash360 2007

[28] KHWoo BH Lee SHHeo et al ldquoAllele frequency of a 24 bpduplication in exon 10 of the CHIT1 gene in the general Koreanpopulation and in Korean patients with Gaucher diseaserdquoJournal of Human Genetics vol 59 no 5 pp 276ndash279 2014

[29] F Fusetti H von Moeller D Houston et al ldquoStructureof human chitotriosidase Implications for specific inhibitordesign and function of mammalian chitinase-like lectinsrdquoJournal of Biological Chemistry vol 277 no 28 pp 25537ndash25544 2002

[30] K B Eide A R Lindbom V G H Eijsink A L Norberg andM Soslashrlie ldquoAnalysis of productive binding modes in the humanchitotriosidaserdquo FEBS Letters vol 587 no 21 pp 3508ndash35132013

[31] L W Stockinger K B Eide A I Dybvik et al ldquoThe effect ofthe carbohydrate binding module on substrate degradation bythe human chitotriosidaserdquo Biochimica et Biophysica Acta vol1854 no 10 pp 1494ndash1501 2015

[32] F Fadel Y Zhao R Cachau et al ldquoNew insights into theenzymatic mechanism of human chitotriosidase (CHIT1) cat-alytic domain by atomic resolution X-ray diffraction andhybrid QMMMrdquo Acta Crystallographica Section D BiologicalCrystallography vol 71 no 7 pp 1455ndash1470 2015

[33] I Labadaridis E Dimitriou M Theodorakis G Kafalidis AVelegraki and H Michelakakis ldquoChitotriosidase in neonateswith fungal and bacterial infectionsrdquo Archives of Disease inChildhood Fetal and Neonatal Edition vol 90 no 6 pp F531ndashF532 2005

[34] Y G Kurt T Cayci P Onguru et al ldquoSerum chitotriosidaseenzyme activity in patients with Crimean-Congo hemorrhagicfeverrdquo Clinical Chemistry and Laboratory Medicine vol 47 no12 pp 1543ndash1547 2009

[35] Y Shibata L A Foster W J Metzger and Q N MyrvikldquoAlveolar macrophage priming by intravenous administrationof chitin particles polymers of N-acetyl-D-glucosamine inmicerdquo Infection and Immunity vol 65 no 5 pp 1734ndash1741 1997

[36] C L Bueter C A Specht and S M Levitz ldquoInnate sensing ofchitin and chitosanrdquo PLoS Pathogens vol 9 no 1 Article IDe1003080 2013

8 Enzyme Research

[37] Y Shibata W J Metzger and Q N Myrvik ldquoChitin particle-induced cell-mediated immunity is inhibited by soluble man-nan mannose receptor-mediated phagocytosis initiates IL-12productionrdquo The Journal of Immunology vol 159 no 5 pp2462ndash2467 1997

[38] L Malaguarnera M Musumeci M Di Rosa A Scuto and SMusumeci ldquoInterferon-gamma tumor necrosis factor-120572 andlipopolysaccharide promote chitotriosidase gene expression inhuman macrophagesrdquo Journal of Clinical Laboratory Analysisvol 19 no 3 pp 128ndash132 2005

[39] O Sharif V N Bolshakov S Raines P Newham and N DPerkins ldquoTranscriptional profiling of the LPS induced NF-120581Bresponse in macrophagesrdquo BMC Immunology vol 8 article 12007

[40] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[41] J P Boyle R Parkhouse and T P Monie ldquoInsights into themolecular basis of the NOD2 signalling pathwayrdquoOpen Biologyvol 4 no 12 Article ID 140178 2014

[42] M van Eijk S S Scheij C P A A van Roomen D SpeijerR G Boot and J M F G Aerts ldquoTLR- and NOD2-dependentregulation of human phagocyte-specific chitotriosidaserdquo FEBSLetters vol 581 no 28 pp 5389ndash5395 2007

[43] L Malaguarnera M Musumeci F Licata M Di Rosa AMessina and S Musumeci ldquoProlactin induces chitotriosidasegene expression in human monocyte-derived macrophagesrdquoImmunology Letters vol 94 no 1-2 pp 57ndash63 2004

[44] M Di Rosa A M Zambito A R Marsullo G Li Volti andL Malaguarnera ldquoProlactin induces chitotriosidase expressionin human macrophages through PTK PI3-K and MAPKpathwaysrdquo Journal of Cellular Biochemistry vol 107 no 5 pp881ndash889 2009

[45] F Martinon L Agostini E Meylan and J Tschopp ldquoIden-tification of bacterial muramyl dipeptide as activator of theNALP3cryopyrin inflammasomerdquo Current Biology vol 14 no21 pp 1929ndash1934 2004

[46] G Prencipe I Caiello S Cherqui et al ldquoInflammasomeactivation by cystine crystals implications for the pathogenesisof cystinosisrdquo Journal of the American Society of Nephrology vol25 no 6 pp 1163ndash1169 2014

[47] K Lieb C Kaltschmidt B Kaltschmidt et al ldquoInterleukin-1120573uses common and distinct signaling pathways for inductionof the interleukin-6 and tumor necrosis factor 120572 genes in thehuman astrocytoma cell line U373rdquo Journal of Neurochemistryvol 66 no 4 pp 1496ndash1503 1996

[48] D Artis and H Spits ldquoThe biology of innate lymphoid cellsrdquoNature vol 517 no 7534 pp 293ndash301 2015

[49] M Di Rosa G Malaguarnera C De Gregorio F DrsquoAmico MCMazzarino and LMalaguarnera ldquoModulation of chitotriosi-dase during macrophage differentiationrdquo Cell Biochemistry andBiophysics vol 66 no 2 pp 239ndash247 2013

[50] M A Elmonem S H Makar L van den Heuvel et al ldquoClinicalutility of chitotriosidase enzyme activity in nephropathic cysti-nosisrdquoOrphanet Journal of Rare Diseases vol 9 no 1 article 1552014

[51] J Correale and M Fiol ldquoChitinase effects on immune cellresponse in neuromyelitis optica and multiple sclerosisrdquo Mul-tiple Sclerosis vol 17 no 5 pp 521ndash531 2011

[52] S Letuve A Kozhich A Humbles et al ldquoLung chitinolyticactivity and chitotriosidase are elevated in chronic obstructive

pulmonary disease and contribute to lung inflammationrdquo TheAmerican Journal of Pathology vol 176 no 2 pp 638ndash649 2010

[53] C G Lee E L Herzog F Ahangari et al ldquoChitinase 1 is abiomarker for and therapeutic target in scleroderma-associatedinterstitial lung disease that augments TGF-1205731 signalingrdquo Jour-nal of Immunology vol 189 no 5 pp 2635ndash2644 2012

[54] M A ElmonemH S Amin R A El-Essawy et al ldquoAssociationof chitotriosidase enzyme activity and genotype with the risk ofnephropathy in type 2 diabetesrdquo Clinical Biochemistry 2015

[55] T E Sutherland R M Maizels and J E Allen ldquoChitinasesand chitinase-like proteins potential therapeutic targets for thetreatment of T-helper type 2 allergiesrdquo Clinical and Experimen-tal Allergy vol 39 no 7 pp 943ndash955 2009

[56] R Shao Q J Cao R B Arenas C Bigelow B Bentley andW Yan ldquoBreast cancer expression of YKL-40 correlates withtumour grade poor differentiation and other cancer markersrdquoBritish Journal of Cancer vol 105 no 8 pp 1203ndash1209 2011

[57] X W Wang C L Cai J M Xu H Jin and Z Y Xu ldquoIncreasedexpression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesisrdquoTumor Biology vol 36 no 2 pp 901ndash907 2015

[58] N Ngernyuang R A Francescone P Jearanaikoon et alldquoChitinase 3 like 1 is associated with tumor angiogenesis incervical cancerrdquo International Journal of Biochemistry and CellBiology vol 51 no 1 pp 45ndash52 2014

[59] X Q Pan C C Shih and J Harday ldquoChitinase induces lysisof MCF-7 cells in culture and of human breast cancer xenograftB11-2 in SCIDmicerdquoAnticancer Research vol 25 no 5 pp 3167ndash3172 2005

[60] B Bonnotte N Larmonier N Favre et al ldquoIdentification oftumor-infiltratingmacrophages as the killers of tumor cells afterimmunization in a rat model systemrdquo Journal of Immunologyvol 167 no 9 pp 5077ndash5083 2001

[61] N N Sanders V G H Eijsink P S van den Pangaart etal ldquoMucolytic activity of bacterial and human chitinasesrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1770 no5 pp 839ndash846 2007

[62] E Shemesh L Deroma B Bembi et al ldquoEnzyme replacementand substrate reduction therapy for Gaucher diseaserdquo CochraneDatabase of Systematic Reviews no 3 Article ID CD0103242015

[63] M Harlander B Salobir M Zupancic M Dolensek T BavcarVodovnik andM Tercelj ldquoSerial chitotriosidasemeasurementsin sarcoidosismdashtwo to five year follow-up studyrdquo RespiratoryMedicine vol 108 no 5 pp 775ndash782 2014

[64] M A Elmonem D I Ramadan M S M Issac L A Selimand S M Elkateb ldquoBlood spot versus plasma chitotriosidase asystematic clinical comparisonrdquo Clinical Biochemistry vol 47no 1-2 pp 38ndash43 2014

[65] M Ries E Schaefer T Luhrs et al ldquoCritical assessment ofchitotriosidase analysis in the rational laboratory diagnosis ofchildren with Gaucher disease and Niemann-Pick disease typeAB and Crdquo Journal of Inherited Metabolic Disease vol 29 no5 pp 647ndash652 2006

[66] A C Vedder J Cox-Brinkman C E M Hollak et al ldquoPlasmachitotriosidase in male Fabry patients a marker for monitor-ing lipid-laden macrophages and their correction by enzymereplacement therapyrdquo Molecular Genetics and Metabolism vol89 no 3 pp 239ndash244 2006

[67] E Dimitriou M Cozar I Mavridou D Grinberg L Vilageliuand H Michelakakis ldquoThe spectrum of Krabbe disease in

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

6 Enzyme Research

Chitotriosidase also mediates many inflammatory pro-cesses through the direct stimulation of different inflamma-tory mediators such as IL-8 MMP9 (collagenase type IV)MCP-1 (CCL2) RANTES (CCL5) and eotaxin (CCL11) thusincreasing the migratory capacity of many immunologicalcells including T lymphocytes macrophages and eosinophils[51 52] Levels of chitotriosidase activities strongly corre-lated with the concentrations of IL-1120573 and TNF-120572 in thebronchoalveolar lavage (BAL) of COPD patients supportingthe hypothesis of a mutual regulation cascade in the pro-duction of these inflammatory mediators [52] Furthermorechitotriosidase was involved in the induction of fibrosis in themurine model of interstitial lung disease as the bleomycin-induced pulmonary fibrosis was significantly reduced in119862ℎ1198941199051minusminus mice and significantly enhanced in lungs from Chit1overexpressing transgenic mice This effect is explained bythe activation of fibroblasts through enhancing TGF-120573 andincreasing the expression of TGF-120573 receptors 1 and 2 leadingto the activation of the Smad and MAPKERK signalingpathways [53] Similar effects have been clinically observedwith other human diseases characterized by faulty tissueremodeling and abnormal healing such as nonalcoholic fattyliver disease bronchial asthma and diabetic nephropathyin which chitotriosidase plasma activities strongly correlatedwith disease progression andor the degree of tissue fibrosis[21 22 54] Targeting the chitotriosidase activation cascadethrough the administration of specific antibodies or pan-chitinase inhibitors significantly ameliorates inflammationand fibrosis in several animal models of autoimmune dis-eases most likely by suppressing the chitotriosidase depen-dent release of different cytokines and chemokines [55]however the safety of this approach in humans is not yetdetermined as it might increase the susceptibility to fungaland protozoal infections

Chitinases and chi-lectins could play a detrimental rolein human cancer development especially CHI3L1 (YKL-40)which has been associatedwith increased tumor angiogenesisand bad prognosis in many human neoplasms such as breastlung and cervical cancers [56ndash58] On the other handchitinases are also believed to have some anticancer cellactivities [59] Macrophages were always considered as aprimary defense line against neoplastic cells but the exactmechanisms beyond this action were not very clear [60]Speculations were made about a combined effect of releasedNO and H

2

O2

however there was no much evidence tosupport this hypothesis [20] Recently bacterial and humanchitinases were both confirmed as having strong synergisticeffects with protease enzymes produced by macrophagesto dissolve mucin [61] This mucolytic activity selectivelyattacked the altered mucin in the cancer cell wall of animalmodels and not the healthy cell mucin [59] It is too earlyto speculate about the therapeutic applications of this obser-vation as many explanatory mechanistic studies are neededto determine the specificity and the exact molecular andchemical targets of this process

Chitotriosidase is currently an established or a candidatescreeningmarker severitymarker andor therapeuticmonitorfor over 40 different diseases inherited and acquired Table 1

provides a summary of human diseases clinically associatedwith macrophage activation and chitotriosidase enzyme pro-duction Being a nonspecific marker of macrophage activa-tion and deficient in about 6 of normal population clearlylimits chitotriosidase usability as a screeningmarker formanydiseases however in established diagnosed nondeficientpatients chitotriosidase is an excellent marker to monitorcompliance and response to treatment [62 63] especiallywhen the treatment targets inflammatory pathways And insome diseases its marked elevations made it also a quitebeneficial screening marker as in Gaucherrsquos disease evenwhen other lysosomal storage disorders are suspected [64]

6 Conclusions

Being a sensitive biomarker of macrophage activation chi-totriosidase activity is currently more and more commonlyused in clinical practice to evaluate the status and responseto treatment of inflammatory based diseases in whichmacrophages play a significant role The interesting mixtureof harmful and beneficial immunological effectsmade humanchitinases and chitotriosidase enzyme an intriguing pointof research If proven safe in humans the development oftargeted therapies either to suppress chitotriosidase activityin autoimmune and inflammatory disorders or to specificallyenhance its targeted activity to kill cancer cells or to potentiateimmunity against certain infections will not be far in thefuture

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] C E M Hollak S van Weely M H J van Oers and J M FG Aerts ldquoMarked elevation of plasma chitotriosidase activityA novel hallmark of Gaucher diseaserdquo The Journal of ClinicalInvestigation vol 93 no 3 pp 1288ndash1292 1994

[2] R N Tharanathan and F S Kittur ldquoChitinmdashthe undisputedbiomolecule of great potentialrdquo Critical Reviews in Food Scienceand Nutrition vol 43 no 1 pp 61ndash87 2003

[3] R G Boot E F C Blommaart E Swart et al ldquoIdentification ofa novel acidic mammalian chitinase distinct from chitotriosi-daserdquo The Journal of Biological Chemistry vol 276 no 9 pp6770ndash6778 2001

[4] A P Bussink D Speijer J M F G Aerts and R G BootldquoEvolution ofmammalian chitinase(-like)members of family 18glycosyl hydrolasesrdquo Genetics vol 177 no 2 pp 959ndash970 2007

[5] R G Boot G H Renkema A Strijland A J Van Zonneveldand J M F G Aerts ldquoCloning of a cDNA encoding chitotriosi-dase a human chitinase produced bymacrophagesrdquoThe Journalof Biological Chemistry vol 270 no 44 pp 26252ndash26256 1995

[6] M A Seibold S Donnelly M Solon et al ldquoChitotriosidase isthe primary active chitinase in the human lung and is modu-lated by genotype and smoking habitrdquo Journal of Allergy andClinical Immunology vol 122 no 5 pp 944ndash950 2008

Enzyme Research 7

[7] L Malaguarnera M Di Rosa A M Zambito N dellrsquoOmbra FNicoletti and M Malaguarnera ldquoChitotriosidase gene expres-sion in Kupffer cells from patients with non-alcoholic fatty liverdiseaserdquo Gut vol 55 no 9 pp 1313ndash1320 2006

[8] R G Boot T A E vanAchterberg B E vanAken et al ldquoStronginduction of members of the chitinase family of proteinsin atherosclerosis chitotriosidase and human cartilage gp-39expressed in lesion macrophagesrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 19 no 3 pp 687ndash694 1999

[9] M Di Rosa D Tibullo M Vecchio et al ldquoDetermination ofchitinases family during osteoclastogenesisrdquo Bone vol 61 pp55ndash63 2014

[10] M Di Rosa D Tibullo D Cambria et al ldquoChitotriosidaseexpression during monocyte-derived dendritic cells differenti-ation and maturationrdquo Inflammation vol 38 no 6 pp 2082ndash2091 2015

[11] L Bouzas J C Guinarte and J C Tutor ldquoChitotriosidaseactivity in plasma and mononuclear and polymorphonuclearleukocyte populationsrdquo Journal of Clinical Laboratory Analysisvol 17 no 6 pp 271ndash275 2003

[12] M van Eijk C P A A van Roomen G H Renkema et alldquoCharacterization of human phagocyte-derived chitotriosidasea component of innate immunityrdquo International Immunologyvol 17 no 11 pp 1505ndash1512 2005

[13] R Barone J Simpore L Malaguarnera S Pignatelli and SMusumeci ldquoPlasma chitotriosidase activity in acute Plasmod-ium falciparummalariardquo Clinica Chimica Acta vol 331 no 1-2pp 79ndash85 2003

[14] E H Choi P A Zimmerman C B Foster et al ldquoGenetic poly-morphisms in molecules of innate immunity and susceptibilityto infection with Wuchereria bancrofti in South Indiardquo Genesand Immunity vol 2 no 5 pp 248ndash253 2001

[15] M Vandevenne V Campisi A Freichels et al ldquoComparativefunctional analysis of the human macrophage chitotriosidaserdquoProtein Science vol 20 no 8 pp 1451ndash1463 2011

[16] P E Verwer C CNotenboomK Eadie et al ldquoA polymorphismin the chitotriosidase gene associated with risk of mycetomadue toMadurellamycetomatismycetoma a retrospective studyrdquoPLOS Neglected Tropical Diseases vol 9 no 9 Article IDe0004061 2015

[17] D L Wiesner C A Specht C K Lee et al ldquoChitin recognitionvia chitotriosidase promotes pathologic type-2 helper T cellresponses to cryptococcal infectionrdquo PLoS Pathogens vol 11 no3 Article ID e1004701 2015

[18] M Di Rosa G Malaguarnera C De Gregorio F Drago and LMalaguarnera ldquoEvaluation of CHI3L-1 and CHIT-1 expressionin differentiated and polarized macrophagesrdquo Inflammationvol 36 no 2 pp 482ndash492 2013

[19] K W Kim J Park J H Lee et al ldquoAssociation of geneticvariation in chitotriosidase with atopy in Korean childrenrdquoAnnals of Allergy Asthma and Immunology vol 110 no 6 pp444ndash449 2013

[20] X-Q Pan ldquoThe mechanism of the anticancer function of M1macrophages and their use in the clinicrdquo Chinese Journal ofCancer vol 31 no 12 pp 557ndash563 2012

[21] A J James L E Reinius M Verhoek et al ldquoThe chitinase pro-teins YKL-40 and chitotriosidase are increased in both asthmaand COPDrdquo American Journal of Respiratory and Critical CareMedicine 2015

[22] M Di Rosa K Mangano C De Gregorio F Nicoletti andL Malaguarnera ldquoAssociation of chitotriosidase genotype with

the development of non-alcoholic fatty liver diseaserdquo Hepatol-ogy Research vol 43 no 3 pp 267ndash275 2013

[23] C Rosen C H Andersson U Andreasson et al ldquoIncreasedlevels of chitotriosidase and YKL-40 in cerebrospinal fluidfrompatients withAlzheimerrsquos diseaserdquoDementia andGeriatricCognitive Disorders Extra vol 4 no 2 pp 297ndash304 2014

[24] AM Varghese A Sharma PMishra et al ldquoChitotriosidasemdashaputative biomarker for sporadic amyotrophic lateral sclerosisrdquoClinical Proteomics vol 10 no 1 article 19 2013

[25] R G Boot G H Renkema M Verhoek et al ldquoThe humanchitotriosidase gene Nature of inherited enzyme deficiencyrdquoThe Journal of Biological Chemistry vol 273 no 40 pp 25680ndash25685 1998

[26] L Malaguarnera J Simpore D A Prodi et al ldquoA 24-bpduplication in exon 10 of human chitotriosidase gene fromthe sub-Saharan to the Mediterranean area role of parasiticdiseases and environmental conditionsrdquo Genes and Immunityvol 4 no 8 pp 570ndash574 2003

[27] P Lee JWaalen K Crain A Smargon and E Beutler ldquoHumanchitotriosidase polymorphisms G354R and A442V associatedwith reduced enzyme activityrdquo Blood Cells Molecules andDiseases vol 39 no 3 pp 353ndash360 2007

[28] KHWoo BH Lee SHHeo et al ldquoAllele frequency of a 24 bpduplication in exon 10 of the CHIT1 gene in the general Koreanpopulation and in Korean patients with Gaucher diseaserdquoJournal of Human Genetics vol 59 no 5 pp 276ndash279 2014

[29] F Fusetti H von Moeller D Houston et al ldquoStructureof human chitotriosidase Implications for specific inhibitordesign and function of mammalian chitinase-like lectinsrdquoJournal of Biological Chemistry vol 277 no 28 pp 25537ndash25544 2002

[30] K B Eide A R Lindbom V G H Eijsink A L Norberg andM Soslashrlie ldquoAnalysis of productive binding modes in the humanchitotriosidaserdquo FEBS Letters vol 587 no 21 pp 3508ndash35132013

[31] L W Stockinger K B Eide A I Dybvik et al ldquoThe effect ofthe carbohydrate binding module on substrate degradation bythe human chitotriosidaserdquo Biochimica et Biophysica Acta vol1854 no 10 pp 1494ndash1501 2015

[32] F Fadel Y Zhao R Cachau et al ldquoNew insights into theenzymatic mechanism of human chitotriosidase (CHIT1) cat-alytic domain by atomic resolution X-ray diffraction andhybrid QMMMrdquo Acta Crystallographica Section D BiologicalCrystallography vol 71 no 7 pp 1455ndash1470 2015

[33] I Labadaridis E Dimitriou M Theodorakis G Kafalidis AVelegraki and H Michelakakis ldquoChitotriosidase in neonateswith fungal and bacterial infectionsrdquo Archives of Disease inChildhood Fetal and Neonatal Edition vol 90 no 6 pp F531ndashF532 2005

[34] Y G Kurt T Cayci P Onguru et al ldquoSerum chitotriosidaseenzyme activity in patients with Crimean-Congo hemorrhagicfeverrdquo Clinical Chemistry and Laboratory Medicine vol 47 no12 pp 1543ndash1547 2009

[35] Y Shibata L A Foster W J Metzger and Q N MyrvikldquoAlveolar macrophage priming by intravenous administrationof chitin particles polymers of N-acetyl-D-glucosamine inmicerdquo Infection and Immunity vol 65 no 5 pp 1734ndash1741 1997

[36] C L Bueter C A Specht and S M Levitz ldquoInnate sensing ofchitin and chitosanrdquo PLoS Pathogens vol 9 no 1 Article IDe1003080 2013

8 Enzyme Research

[37] Y Shibata W J Metzger and Q N Myrvik ldquoChitin particle-induced cell-mediated immunity is inhibited by soluble man-nan mannose receptor-mediated phagocytosis initiates IL-12productionrdquo The Journal of Immunology vol 159 no 5 pp2462ndash2467 1997

[38] L Malaguarnera M Musumeci M Di Rosa A Scuto and SMusumeci ldquoInterferon-gamma tumor necrosis factor-120572 andlipopolysaccharide promote chitotriosidase gene expression inhuman macrophagesrdquo Journal of Clinical Laboratory Analysisvol 19 no 3 pp 128ndash132 2005

[39] O Sharif V N Bolshakov S Raines P Newham and N DPerkins ldquoTranscriptional profiling of the LPS induced NF-120581Bresponse in macrophagesrdquo BMC Immunology vol 8 article 12007

[40] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[41] J P Boyle R Parkhouse and T P Monie ldquoInsights into themolecular basis of the NOD2 signalling pathwayrdquoOpen Biologyvol 4 no 12 Article ID 140178 2014

[42] M van Eijk S S Scheij C P A A van Roomen D SpeijerR G Boot and J M F G Aerts ldquoTLR- and NOD2-dependentregulation of human phagocyte-specific chitotriosidaserdquo FEBSLetters vol 581 no 28 pp 5389ndash5395 2007

[43] L Malaguarnera M Musumeci F Licata M Di Rosa AMessina and S Musumeci ldquoProlactin induces chitotriosidasegene expression in human monocyte-derived macrophagesrdquoImmunology Letters vol 94 no 1-2 pp 57ndash63 2004

[44] M Di Rosa A M Zambito A R Marsullo G Li Volti andL Malaguarnera ldquoProlactin induces chitotriosidase expressionin human macrophages through PTK PI3-K and MAPKpathwaysrdquo Journal of Cellular Biochemistry vol 107 no 5 pp881ndash889 2009

[45] F Martinon L Agostini E Meylan and J Tschopp ldquoIden-tification of bacterial muramyl dipeptide as activator of theNALP3cryopyrin inflammasomerdquo Current Biology vol 14 no21 pp 1929ndash1934 2004

[46] G Prencipe I Caiello S Cherqui et al ldquoInflammasomeactivation by cystine crystals implications for the pathogenesisof cystinosisrdquo Journal of the American Society of Nephrology vol25 no 6 pp 1163ndash1169 2014

[47] K Lieb C Kaltschmidt B Kaltschmidt et al ldquoInterleukin-1120573uses common and distinct signaling pathways for inductionof the interleukin-6 and tumor necrosis factor 120572 genes in thehuman astrocytoma cell line U373rdquo Journal of Neurochemistryvol 66 no 4 pp 1496ndash1503 1996

[48] D Artis and H Spits ldquoThe biology of innate lymphoid cellsrdquoNature vol 517 no 7534 pp 293ndash301 2015

[49] M Di Rosa G Malaguarnera C De Gregorio F DrsquoAmico MCMazzarino and LMalaguarnera ldquoModulation of chitotriosi-dase during macrophage differentiationrdquo Cell Biochemistry andBiophysics vol 66 no 2 pp 239ndash247 2013

[50] M A Elmonem S H Makar L van den Heuvel et al ldquoClinicalutility of chitotriosidase enzyme activity in nephropathic cysti-nosisrdquoOrphanet Journal of Rare Diseases vol 9 no 1 article 1552014

[51] J Correale and M Fiol ldquoChitinase effects on immune cellresponse in neuromyelitis optica and multiple sclerosisrdquo Mul-tiple Sclerosis vol 17 no 5 pp 521ndash531 2011

[52] S Letuve A Kozhich A Humbles et al ldquoLung chitinolyticactivity and chitotriosidase are elevated in chronic obstructive

pulmonary disease and contribute to lung inflammationrdquo TheAmerican Journal of Pathology vol 176 no 2 pp 638ndash649 2010

[53] C G Lee E L Herzog F Ahangari et al ldquoChitinase 1 is abiomarker for and therapeutic target in scleroderma-associatedinterstitial lung disease that augments TGF-1205731 signalingrdquo Jour-nal of Immunology vol 189 no 5 pp 2635ndash2644 2012

[54] M A ElmonemH S Amin R A El-Essawy et al ldquoAssociationof chitotriosidase enzyme activity and genotype with the risk ofnephropathy in type 2 diabetesrdquo Clinical Biochemistry 2015

[55] T E Sutherland R M Maizels and J E Allen ldquoChitinasesand chitinase-like proteins potential therapeutic targets for thetreatment of T-helper type 2 allergiesrdquo Clinical and Experimen-tal Allergy vol 39 no 7 pp 943ndash955 2009

[56] R Shao Q J Cao R B Arenas C Bigelow B Bentley andW Yan ldquoBreast cancer expression of YKL-40 correlates withtumour grade poor differentiation and other cancer markersrdquoBritish Journal of Cancer vol 105 no 8 pp 1203ndash1209 2011

[57] X W Wang C L Cai J M Xu H Jin and Z Y Xu ldquoIncreasedexpression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesisrdquoTumor Biology vol 36 no 2 pp 901ndash907 2015

[58] N Ngernyuang R A Francescone P Jearanaikoon et alldquoChitinase 3 like 1 is associated with tumor angiogenesis incervical cancerrdquo International Journal of Biochemistry and CellBiology vol 51 no 1 pp 45ndash52 2014

[59] X Q Pan C C Shih and J Harday ldquoChitinase induces lysisof MCF-7 cells in culture and of human breast cancer xenograftB11-2 in SCIDmicerdquoAnticancer Research vol 25 no 5 pp 3167ndash3172 2005

[60] B Bonnotte N Larmonier N Favre et al ldquoIdentification oftumor-infiltratingmacrophages as the killers of tumor cells afterimmunization in a rat model systemrdquo Journal of Immunologyvol 167 no 9 pp 5077ndash5083 2001

[61] N N Sanders V G H Eijsink P S van den Pangaart etal ldquoMucolytic activity of bacterial and human chitinasesrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1770 no5 pp 839ndash846 2007

[62] E Shemesh L Deroma B Bembi et al ldquoEnzyme replacementand substrate reduction therapy for Gaucher diseaserdquo CochraneDatabase of Systematic Reviews no 3 Article ID CD0103242015

[63] M Harlander B Salobir M Zupancic M Dolensek T BavcarVodovnik andM Tercelj ldquoSerial chitotriosidasemeasurementsin sarcoidosismdashtwo to five year follow-up studyrdquo RespiratoryMedicine vol 108 no 5 pp 775ndash782 2014

[64] M A Elmonem D I Ramadan M S M Issac L A Selimand S M Elkateb ldquoBlood spot versus plasma chitotriosidase asystematic clinical comparisonrdquo Clinical Biochemistry vol 47no 1-2 pp 38ndash43 2014

[65] M Ries E Schaefer T Luhrs et al ldquoCritical assessment ofchitotriosidase analysis in the rational laboratory diagnosis ofchildren with Gaucher disease and Niemann-Pick disease typeAB and Crdquo Journal of Inherited Metabolic Disease vol 29 no5 pp 647ndash652 2006

[66] A C Vedder J Cox-Brinkman C E M Hollak et al ldquoPlasmachitotriosidase in male Fabry patients a marker for monitor-ing lipid-laden macrophages and their correction by enzymereplacement therapyrdquo Molecular Genetics and Metabolism vol89 no 3 pp 239ndash244 2006

[67] E Dimitriou M Cozar I Mavridou D Grinberg L Vilageliuand H Michelakakis ldquoThe spectrum of Krabbe disease in

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Enzyme Research 7

[7] L Malaguarnera M Di Rosa A M Zambito N dellrsquoOmbra FNicoletti and M Malaguarnera ldquoChitotriosidase gene expres-sion in Kupffer cells from patients with non-alcoholic fatty liverdiseaserdquo Gut vol 55 no 9 pp 1313ndash1320 2006

[8] R G Boot T A E vanAchterberg B E vanAken et al ldquoStronginduction of members of the chitinase family of proteinsin atherosclerosis chitotriosidase and human cartilage gp-39expressed in lesion macrophagesrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 19 no 3 pp 687ndash694 1999

[9] M Di Rosa D Tibullo M Vecchio et al ldquoDetermination ofchitinases family during osteoclastogenesisrdquo Bone vol 61 pp55ndash63 2014

[10] M Di Rosa D Tibullo D Cambria et al ldquoChitotriosidaseexpression during monocyte-derived dendritic cells differenti-ation and maturationrdquo Inflammation vol 38 no 6 pp 2082ndash2091 2015

[11] L Bouzas J C Guinarte and J C Tutor ldquoChitotriosidaseactivity in plasma and mononuclear and polymorphonuclearleukocyte populationsrdquo Journal of Clinical Laboratory Analysisvol 17 no 6 pp 271ndash275 2003

[12] M van Eijk C P A A van Roomen G H Renkema et alldquoCharacterization of human phagocyte-derived chitotriosidasea component of innate immunityrdquo International Immunologyvol 17 no 11 pp 1505ndash1512 2005

[13] R Barone J Simpore L Malaguarnera S Pignatelli and SMusumeci ldquoPlasma chitotriosidase activity in acute Plasmod-ium falciparummalariardquo Clinica Chimica Acta vol 331 no 1-2pp 79ndash85 2003

[14] E H Choi P A Zimmerman C B Foster et al ldquoGenetic poly-morphisms in molecules of innate immunity and susceptibilityto infection with Wuchereria bancrofti in South Indiardquo Genesand Immunity vol 2 no 5 pp 248ndash253 2001

[15] M Vandevenne V Campisi A Freichels et al ldquoComparativefunctional analysis of the human macrophage chitotriosidaserdquoProtein Science vol 20 no 8 pp 1451ndash1463 2011

[16] P E Verwer C CNotenboomK Eadie et al ldquoA polymorphismin the chitotriosidase gene associated with risk of mycetomadue toMadurellamycetomatismycetoma a retrospective studyrdquoPLOS Neglected Tropical Diseases vol 9 no 9 Article IDe0004061 2015

[17] D L Wiesner C A Specht C K Lee et al ldquoChitin recognitionvia chitotriosidase promotes pathologic type-2 helper T cellresponses to cryptococcal infectionrdquo PLoS Pathogens vol 11 no3 Article ID e1004701 2015

[18] M Di Rosa G Malaguarnera C De Gregorio F Drago and LMalaguarnera ldquoEvaluation of CHI3L-1 and CHIT-1 expressionin differentiated and polarized macrophagesrdquo Inflammationvol 36 no 2 pp 482ndash492 2013

[19] K W Kim J Park J H Lee et al ldquoAssociation of geneticvariation in chitotriosidase with atopy in Korean childrenrdquoAnnals of Allergy Asthma and Immunology vol 110 no 6 pp444ndash449 2013

[20] X-Q Pan ldquoThe mechanism of the anticancer function of M1macrophages and their use in the clinicrdquo Chinese Journal ofCancer vol 31 no 12 pp 557ndash563 2012

[21] A J James L E Reinius M Verhoek et al ldquoThe chitinase pro-teins YKL-40 and chitotriosidase are increased in both asthmaand COPDrdquo American Journal of Respiratory and Critical CareMedicine 2015

[22] M Di Rosa K Mangano C De Gregorio F Nicoletti andL Malaguarnera ldquoAssociation of chitotriosidase genotype with

the development of non-alcoholic fatty liver diseaserdquo Hepatol-ogy Research vol 43 no 3 pp 267ndash275 2013

[23] C Rosen C H Andersson U Andreasson et al ldquoIncreasedlevels of chitotriosidase and YKL-40 in cerebrospinal fluidfrompatients withAlzheimerrsquos diseaserdquoDementia andGeriatricCognitive Disorders Extra vol 4 no 2 pp 297ndash304 2014

[24] AM Varghese A Sharma PMishra et al ldquoChitotriosidasemdashaputative biomarker for sporadic amyotrophic lateral sclerosisrdquoClinical Proteomics vol 10 no 1 article 19 2013

[25] R G Boot G H Renkema M Verhoek et al ldquoThe humanchitotriosidase gene Nature of inherited enzyme deficiencyrdquoThe Journal of Biological Chemistry vol 273 no 40 pp 25680ndash25685 1998

[26] L Malaguarnera J Simpore D A Prodi et al ldquoA 24-bpduplication in exon 10 of human chitotriosidase gene fromthe sub-Saharan to the Mediterranean area role of parasiticdiseases and environmental conditionsrdquo Genes and Immunityvol 4 no 8 pp 570ndash574 2003

[27] P Lee JWaalen K Crain A Smargon and E Beutler ldquoHumanchitotriosidase polymorphisms G354R and A442V associatedwith reduced enzyme activityrdquo Blood Cells Molecules andDiseases vol 39 no 3 pp 353ndash360 2007

[28] KHWoo BH Lee SHHeo et al ldquoAllele frequency of a 24 bpduplication in exon 10 of the CHIT1 gene in the general Koreanpopulation and in Korean patients with Gaucher diseaserdquoJournal of Human Genetics vol 59 no 5 pp 276ndash279 2014

[29] F Fusetti H von Moeller D Houston et al ldquoStructureof human chitotriosidase Implications for specific inhibitordesign and function of mammalian chitinase-like lectinsrdquoJournal of Biological Chemistry vol 277 no 28 pp 25537ndash25544 2002

[30] K B Eide A R Lindbom V G H Eijsink A L Norberg andM Soslashrlie ldquoAnalysis of productive binding modes in the humanchitotriosidaserdquo FEBS Letters vol 587 no 21 pp 3508ndash35132013

[31] L W Stockinger K B Eide A I Dybvik et al ldquoThe effect ofthe carbohydrate binding module on substrate degradation bythe human chitotriosidaserdquo Biochimica et Biophysica Acta vol1854 no 10 pp 1494ndash1501 2015

[32] F Fadel Y Zhao R Cachau et al ldquoNew insights into theenzymatic mechanism of human chitotriosidase (CHIT1) cat-alytic domain by atomic resolution X-ray diffraction andhybrid QMMMrdquo Acta Crystallographica Section D BiologicalCrystallography vol 71 no 7 pp 1455ndash1470 2015

[33] I Labadaridis E Dimitriou M Theodorakis G Kafalidis AVelegraki and H Michelakakis ldquoChitotriosidase in neonateswith fungal and bacterial infectionsrdquo Archives of Disease inChildhood Fetal and Neonatal Edition vol 90 no 6 pp F531ndashF532 2005

[34] Y G Kurt T Cayci P Onguru et al ldquoSerum chitotriosidaseenzyme activity in patients with Crimean-Congo hemorrhagicfeverrdquo Clinical Chemistry and Laboratory Medicine vol 47 no12 pp 1543ndash1547 2009

[35] Y Shibata L A Foster W J Metzger and Q N MyrvikldquoAlveolar macrophage priming by intravenous administrationof chitin particles polymers of N-acetyl-D-glucosamine inmicerdquo Infection and Immunity vol 65 no 5 pp 1734ndash1741 1997

[36] C L Bueter C A Specht and S M Levitz ldquoInnate sensing ofchitin and chitosanrdquo PLoS Pathogens vol 9 no 1 Article IDe1003080 2013

8 Enzyme Research

[37] Y Shibata W J Metzger and Q N Myrvik ldquoChitin particle-induced cell-mediated immunity is inhibited by soluble man-nan mannose receptor-mediated phagocytosis initiates IL-12productionrdquo The Journal of Immunology vol 159 no 5 pp2462ndash2467 1997

[38] L Malaguarnera M Musumeci M Di Rosa A Scuto and SMusumeci ldquoInterferon-gamma tumor necrosis factor-120572 andlipopolysaccharide promote chitotriosidase gene expression inhuman macrophagesrdquo Journal of Clinical Laboratory Analysisvol 19 no 3 pp 128ndash132 2005

[39] O Sharif V N Bolshakov S Raines P Newham and N DPerkins ldquoTranscriptional profiling of the LPS induced NF-120581Bresponse in macrophagesrdquo BMC Immunology vol 8 article 12007

[40] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[41] J P Boyle R Parkhouse and T P Monie ldquoInsights into themolecular basis of the NOD2 signalling pathwayrdquoOpen Biologyvol 4 no 12 Article ID 140178 2014

[42] M van Eijk S S Scheij C P A A van Roomen D SpeijerR G Boot and J M F G Aerts ldquoTLR- and NOD2-dependentregulation of human phagocyte-specific chitotriosidaserdquo FEBSLetters vol 581 no 28 pp 5389ndash5395 2007

[43] L Malaguarnera M Musumeci F Licata M Di Rosa AMessina and S Musumeci ldquoProlactin induces chitotriosidasegene expression in human monocyte-derived macrophagesrdquoImmunology Letters vol 94 no 1-2 pp 57ndash63 2004

[44] M Di Rosa A M Zambito A R Marsullo G Li Volti andL Malaguarnera ldquoProlactin induces chitotriosidase expressionin human macrophages through PTK PI3-K and MAPKpathwaysrdquo Journal of Cellular Biochemistry vol 107 no 5 pp881ndash889 2009

[45] F Martinon L Agostini E Meylan and J Tschopp ldquoIden-tification of bacterial muramyl dipeptide as activator of theNALP3cryopyrin inflammasomerdquo Current Biology vol 14 no21 pp 1929ndash1934 2004

[46] G Prencipe I Caiello S Cherqui et al ldquoInflammasomeactivation by cystine crystals implications for the pathogenesisof cystinosisrdquo Journal of the American Society of Nephrology vol25 no 6 pp 1163ndash1169 2014

[47] K Lieb C Kaltschmidt B Kaltschmidt et al ldquoInterleukin-1120573uses common and distinct signaling pathways for inductionof the interleukin-6 and tumor necrosis factor 120572 genes in thehuman astrocytoma cell line U373rdquo Journal of Neurochemistryvol 66 no 4 pp 1496ndash1503 1996

[48] D Artis and H Spits ldquoThe biology of innate lymphoid cellsrdquoNature vol 517 no 7534 pp 293ndash301 2015

[49] M Di Rosa G Malaguarnera C De Gregorio F DrsquoAmico MCMazzarino and LMalaguarnera ldquoModulation of chitotriosi-dase during macrophage differentiationrdquo Cell Biochemistry andBiophysics vol 66 no 2 pp 239ndash247 2013

[50] M A Elmonem S H Makar L van den Heuvel et al ldquoClinicalutility of chitotriosidase enzyme activity in nephropathic cysti-nosisrdquoOrphanet Journal of Rare Diseases vol 9 no 1 article 1552014

[51] J Correale and M Fiol ldquoChitinase effects on immune cellresponse in neuromyelitis optica and multiple sclerosisrdquo Mul-tiple Sclerosis vol 17 no 5 pp 521ndash531 2011

[52] S Letuve A Kozhich A Humbles et al ldquoLung chitinolyticactivity and chitotriosidase are elevated in chronic obstructive

pulmonary disease and contribute to lung inflammationrdquo TheAmerican Journal of Pathology vol 176 no 2 pp 638ndash649 2010

[53] C G Lee E L Herzog F Ahangari et al ldquoChitinase 1 is abiomarker for and therapeutic target in scleroderma-associatedinterstitial lung disease that augments TGF-1205731 signalingrdquo Jour-nal of Immunology vol 189 no 5 pp 2635ndash2644 2012

[54] M A ElmonemH S Amin R A El-Essawy et al ldquoAssociationof chitotriosidase enzyme activity and genotype with the risk ofnephropathy in type 2 diabetesrdquo Clinical Biochemistry 2015

[55] T E Sutherland R M Maizels and J E Allen ldquoChitinasesand chitinase-like proteins potential therapeutic targets for thetreatment of T-helper type 2 allergiesrdquo Clinical and Experimen-tal Allergy vol 39 no 7 pp 943ndash955 2009

[56] R Shao Q J Cao R B Arenas C Bigelow B Bentley andW Yan ldquoBreast cancer expression of YKL-40 correlates withtumour grade poor differentiation and other cancer markersrdquoBritish Journal of Cancer vol 105 no 8 pp 1203ndash1209 2011

[57] X W Wang C L Cai J M Xu H Jin and Z Y Xu ldquoIncreasedexpression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesisrdquoTumor Biology vol 36 no 2 pp 901ndash907 2015

[58] N Ngernyuang R A Francescone P Jearanaikoon et alldquoChitinase 3 like 1 is associated with tumor angiogenesis incervical cancerrdquo International Journal of Biochemistry and CellBiology vol 51 no 1 pp 45ndash52 2014

[59] X Q Pan C C Shih and J Harday ldquoChitinase induces lysisof MCF-7 cells in culture and of human breast cancer xenograftB11-2 in SCIDmicerdquoAnticancer Research vol 25 no 5 pp 3167ndash3172 2005

[60] B Bonnotte N Larmonier N Favre et al ldquoIdentification oftumor-infiltratingmacrophages as the killers of tumor cells afterimmunization in a rat model systemrdquo Journal of Immunologyvol 167 no 9 pp 5077ndash5083 2001

[61] N N Sanders V G H Eijsink P S van den Pangaart etal ldquoMucolytic activity of bacterial and human chitinasesrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1770 no5 pp 839ndash846 2007

[62] E Shemesh L Deroma B Bembi et al ldquoEnzyme replacementand substrate reduction therapy for Gaucher diseaserdquo CochraneDatabase of Systematic Reviews no 3 Article ID CD0103242015

[63] M Harlander B Salobir M Zupancic M Dolensek T BavcarVodovnik andM Tercelj ldquoSerial chitotriosidasemeasurementsin sarcoidosismdashtwo to five year follow-up studyrdquo RespiratoryMedicine vol 108 no 5 pp 775ndash782 2014

[64] M A Elmonem D I Ramadan M S M Issac L A Selimand S M Elkateb ldquoBlood spot versus plasma chitotriosidase asystematic clinical comparisonrdquo Clinical Biochemistry vol 47no 1-2 pp 38ndash43 2014

[65] M Ries E Schaefer T Luhrs et al ldquoCritical assessment ofchitotriosidase analysis in the rational laboratory diagnosis ofchildren with Gaucher disease and Niemann-Pick disease typeAB and Crdquo Journal of Inherited Metabolic Disease vol 29 no5 pp 647ndash652 2006

[66] A C Vedder J Cox-Brinkman C E M Hollak et al ldquoPlasmachitotriosidase in male Fabry patients a marker for monitor-ing lipid-laden macrophages and their correction by enzymereplacement therapyrdquo Molecular Genetics and Metabolism vol89 no 3 pp 239ndash244 2006

[67] E Dimitriou M Cozar I Mavridou D Grinberg L Vilageliuand H Michelakakis ldquoThe spectrum of Krabbe disease in

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

8 Enzyme Research

[37] Y Shibata W J Metzger and Q N Myrvik ldquoChitin particle-induced cell-mediated immunity is inhibited by soluble man-nan mannose receptor-mediated phagocytosis initiates IL-12productionrdquo The Journal of Immunology vol 159 no 5 pp2462ndash2467 1997

[38] L Malaguarnera M Musumeci M Di Rosa A Scuto and SMusumeci ldquoInterferon-gamma tumor necrosis factor-120572 andlipopolysaccharide promote chitotriosidase gene expression inhuman macrophagesrdquo Journal of Clinical Laboratory Analysisvol 19 no 3 pp 128ndash132 2005

[39] O Sharif V N Bolshakov S Raines P Newham and N DPerkins ldquoTranscriptional profiling of the LPS induced NF-120581Bresponse in macrophagesrdquo BMC Immunology vol 8 article 12007

[40] K Schroder P J Hertzog T Ravasi and D A HumeldquoInterferon-120574 an overview of signals mechanisms and func-tionsrdquo Journal of Leukocyte Biology vol 75 no 2 pp 163ndash1892004

[41] J P Boyle R Parkhouse and T P Monie ldquoInsights into themolecular basis of the NOD2 signalling pathwayrdquoOpen Biologyvol 4 no 12 Article ID 140178 2014

[42] M van Eijk S S Scheij C P A A van Roomen D SpeijerR G Boot and J M F G Aerts ldquoTLR- and NOD2-dependentregulation of human phagocyte-specific chitotriosidaserdquo FEBSLetters vol 581 no 28 pp 5389ndash5395 2007

[43] L Malaguarnera M Musumeci F Licata M Di Rosa AMessina and S Musumeci ldquoProlactin induces chitotriosidasegene expression in human monocyte-derived macrophagesrdquoImmunology Letters vol 94 no 1-2 pp 57ndash63 2004

[44] M Di Rosa A M Zambito A R Marsullo G Li Volti andL Malaguarnera ldquoProlactin induces chitotriosidase expressionin human macrophages through PTK PI3-K and MAPKpathwaysrdquo Journal of Cellular Biochemistry vol 107 no 5 pp881ndash889 2009

[45] F Martinon L Agostini E Meylan and J Tschopp ldquoIden-tification of bacterial muramyl dipeptide as activator of theNALP3cryopyrin inflammasomerdquo Current Biology vol 14 no21 pp 1929ndash1934 2004

[46] G Prencipe I Caiello S Cherqui et al ldquoInflammasomeactivation by cystine crystals implications for the pathogenesisof cystinosisrdquo Journal of the American Society of Nephrology vol25 no 6 pp 1163ndash1169 2014

[47] K Lieb C Kaltschmidt B Kaltschmidt et al ldquoInterleukin-1120573uses common and distinct signaling pathways for inductionof the interleukin-6 and tumor necrosis factor 120572 genes in thehuman astrocytoma cell line U373rdquo Journal of Neurochemistryvol 66 no 4 pp 1496ndash1503 1996

[48] D Artis and H Spits ldquoThe biology of innate lymphoid cellsrdquoNature vol 517 no 7534 pp 293ndash301 2015

[49] M Di Rosa G Malaguarnera C De Gregorio F DrsquoAmico MCMazzarino and LMalaguarnera ldquoModulation of chitotriosi-dase during macrophage differentiationrdquo Cell Biochemistry andBiophysics vol 66 no 2 pp 239ndash247 2013

[50] M A Elmonem S H Makar L van den Heuvel et al ldquoClinicalutility of chitotriosidase enzyme activity in nephropathic cysti-nosisrdquoOrphanet Journal of Rare Diseases vol 9 no 1 article 1552014

[51] J Correale and M Fiol ldquoChitinase effects on immune cellresponse in neuromyelitis optica and multiple sclerosisrdquo Mul-tiple Sclerosis vol 17 no 5 pp 521ndash531 2011

[52] S Letuve A Kozhich A Humbles et al ldquoLung chitinolyticactivity and chitotriosidase are elevated in chronic obstructive

pulmonary disease and contribute to lung inflammationrdquo TheAmerican Journal of Pathology vol 176 no 2 pp 638ndash649 2010

[53] C G Lee E L Herzog F Ahangari et al ldquoChitinase 1 is abiomarker for and therapeutic target in scleroderma-associatedinterstitial lung disease that augments TGF-1205731 signalingrdquo Jour-nal of Immunology vol 189 no 5 pp 2635ndash2644 2012

[54] M A ElmonemH S Amin R A El-Essawy et al ldquoAssociationof chitotriosidase enzyme activity and genotype with the risk ofnephropathy in type 2 diabetesrdquo Clinical Biochemistry 2015

[55] T E Sutherland R M Maizels and J E Allen ldquoChitinasesand chitinase-like proteins potential therapeutic targets for thetreatment of T-helper type 2 allergiesrdquo Clinical and Experimen-tal Allergy vol 39 no 7 pp 943ndash955 2009

[56] R Shao Q J Cao R B Arenas C Bigelow B Bentley andW Yan ldquoBreast cancer expression of YKL-40 correlates withtumour grade poor differentiation and other cancer markersrdquoBritish Journal of Cancer vol 105 no 8 pp 1203ndash1209 2011

[57] X W Wang C L Cai J M Xu H Jin and Z Y Xu ldquoIncreasedexpression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesisrdquoTumor Biology vol 36 no 2 pp 901ndash907 2015

[58] N Ngernyuang R A Francescone P Jearanaikoon et alldquoChitinase 3 like 1 is associated with tumor angiogenesis incervical cancerrdquo International Journal of Biochemistry and CellBiology vol 51 no 1 pp 45ndash52 2014

[59] X Q Pan C C Shih and J Harday ldquoChitinase induces lysisof MCF-7 cells in culture and of human breast cancer xenograftB11-2 in SCIDmicerdquoAnticancer Research vol 25 no 5 pp 3167ndash3172 2005

[60] B Bonnotte N Larmonier N Favre et al ldquoIdentification oftumor-infiltratingmacrophages as the killers of tumor cells afterimmunization in a rat model systemrdquo Journal of Immunologyvol 167 no 9 pp 5077ndash5083 2001

[61] N N Sanders V G H Eijsink P S van den Pangaart etal ldquoMucolytic activity of bacterial and human chitinasesrdquoBiochimica et Biophysica ActamdashGeneral Subjects vol 1770 no5 pp 839ndash846 2007

[62] E Shemesh L Deroma B Bembi et al ldquoEnzyme replacementand substrate reduction therapy for Gaucher diseaserdquo CochraneDatabase of Systematic Reviews no 3 Article ID CD0103242015

[63] M Harlander B Salobir M Zupancic M Dolensek T BavcarVodovnik andM Tercelj ldquoSerial chitotriosidasemeasurementsin sarcoidosismdashtwo to five year follow-up studyrdquo RespiratoryMedicine vol 108 no 5 pp 775ndash782 2014

[64] M A Elmonem D I Ramadan M S M Issac L A Selimand S M Elkateb ldquoBlood spot versus plasma chitotriosidase asystematic clinical comparisonrdquo Clinical Biochemistry vol 47no 1-2 pp 38ndash43 2014

[65] M Ries E Schaefer T Luhrs et al ldquoCritical assessment ofchitotriosidase analysis in the rational laboratory diagnosis ofchildren with Gaucher disease and Niemann-Pick disease typeAB and Crdquo Journal of Inherited Metabolic Disease vol 29 no5 pp 647ndash652 2006

[66] A C Vedder J Cox-Brinkman C E M Hollak et al ldquoPlasmachitotriosidase in male Fabry patients a marker for monitor-ing lipid-laden macrophages and their correction by enzymereplacement therapyrdquo Molecular Genetics and Metabolism vol89 no 3 pp 239ndash244 2006

[67] E Dimitriou M Cozar I Mavridou D Grinberg L Vilageliuand H Michelakakis ldquoThe spectrum of Krabbe disease in

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Enzyme Research 9

Greece biochemical and molecular findingsrdquo JIMD Reports2015

[68] Z Reiner O Guardamagna D Nair et al ldquoLysosomal acidlipase deficiencymdashan under-recognized cause of dyslipidaemiaand liver dysfunctionrdquo Atherosclerosis vol 235 no 1 pp 21ndash302014

[69] M Muranjan S Agarwal K Lahiri and M Bashyam ldquoNovelbiochemical abnormalities and genotype in Farber diseaserdquoIndian Pediatrics vol 49 no 4 pp 320ndash322 2012

[70] A Wajner K Michelin M G Burin et al ldquoComparisonbetween the biochemical properties of plasma chitotriosidasefrom normal individuals and from patients with Gaucherdisease GM1-gangliosidosis Krabbe disease and heterozygotesfor Gaucher diseaserdquo Clinical Biochemistry vol 40 no 5-6 pp365ndash369 2007

[71] A Caciotti M Di Rocco M Filocamo et al ldquoType II sialidosisreview of the clinical spectrum and identification of a newsplicing defect with chitotriosidase assessment in two patientsrdquoJournal of Neurology vol 256 no 11 pp 1911ndash1915 2009

[72] C Tasci S Tapan S Ozkaya et al ldquoEfficacy of serum chi-totriosidase activity in early treatment of patients with activetuberculosis and a negative sputum smearrdquo Therapeutics andClinical Risk Management vol 8 pp 369ndash372 2012

[73] O Coskun S Oter H Yaman S Kilic I Kurt and C P EyigunldquoEvaluating the validity of serum neopterin and chitotriosidaselevels in follow-up brucellosis patientsrdquo Internal Medicine vol49 no 12 pp 1111ndash1118 2010

[74] A Iyer M van Eijk E Silva et al ldquoIncreased chitotriosidaseactivity in serum of leprosy patients association with bacillaryleprosyrdquo Clinical Immunology vol 131 no 3 pp 501ndash509 2009

[75] E Bargagli M Margollicci A Luddi et al ldquoChitotriosidaseactivity in patients with interstitial lung diseasesrdquo RespiratoryMedicine vol 101 no 10 pp 2176ndash2181 2007

[76] A Sonmez C Haymana S Tapan et al ldquoChitotriosidaseactivity predicts endothelial dysfunction in type-2 diabetesmellitusrdquo Endocrine vol 37 no 3 pp 455ndash459 2010

[77] M Artieda A Cenarro A Ganan et al ldquoSerum chitotriosidaseactivity is increased in subjects with atherosclerosis diseaserdquoArteriosclerosis Thrombosis and Vascular Biology vol 23 no9 pp 1645ndash1652 2003

[78] T Kologlu S K Ucar E Levent Y D Akcay M Coker andE Y Sozmen ldquoChitotriosidase as a possible marker of clinicallyevidenced atherosclerosis in dyslipidemic childrenrdquo Journal ofPediatric Endocrinology andMetabolism vol 27 no 7-8 pp 701ndash708 2014

[79] A Bustamante C Dominguez V Rodriguez-Sureda et alldquoPrognostic value of plasma chitotriosidase activity in acutestroke patientsrdquo International Journal of Stroke vol 9 no 7 pp910ndash916 2014

[80] B S Yildiz B Barutcuoglu Y I Alihanoglu et al ldquoSerumchitotriosidase activity in acute coronary syndromerdquo Journal ofAtherosclerosis and Thrombosis vol 20 no 2 pp 134ndash141 2013

[81] M R Safarinejad and S Safarinejad ldquoPlasma chitotriosidaseactivity and arteriogenic erectile dysfunction association withthe presence severity and durationrdquo The Journal of SexualMedicine 2010

[82] V Pagliardini S Pagliardini L Corrado et al ldquoChitotriosidaseand lysosomal enzymes as potential biomarkers of diseaseprogression in amyotrophic lateral sclerosis a survey clinic-based studyrdquo Journal of the Neurological Sciences vol 348 no1-2 pp 245ndash250 2015

[83] B Olsson CMalmestrom H Basun et al ldquoExtreme stability ofchitotriosidase in cerebrospinal fluid makes it a suitable markerfor microglial activation in clinical trialsrdquo Journal of AlzheimerrsquosDisease vol 32 no 2 pp 273ndash276 2012

[84] P J Orchard T Lund W Miller et al ldquoChitotriosidase asa biomarker of cerebral adrenoleukodystrophyrdquo Journal ofNeuroinflammation vol 8 article 144 2011

[85] A Aydogdu I Tasci S Tapan et al ldquoWomen with polycysticovary syndrome have increased plasma chitotriosidase activitya pathophysiological link between inflammation and impairedinsulin sensitivityrdquo Experimental and Clinical Endocrinologyand Diabetes vol 120 no 5 pp 261ndash265 2012

[86] I Alanbay H Coksuer C M Ercan et al ldquoChitotriosidaselevels in patients with severe endometriosisrdquo GynecologicalEndocrinology vol 28 no 3 pp 220ndash223 2012

[87] U Aksoy H Aksoy G Acmaz M Babayigit and O Kan-demir ldquoUmbilical artery serum chitotriosidase concentrationin pregnancies complicated by preeclampsia and relationshipbetween chitotriosidase levels and fetal blood flow velocityrdquoHypertension in Pregnancy vol 32 no 4 pp 401ndash409 2013

[88] A TaylanOGurler B Toprak et al ldquoS1000A12 chitotriosidaseand resolvin D1 as potential biomarkers of familial mediter-ranean feverrdquo Journal of Korean Medical Science vol 30 no 9pp 1241ndash1245 2015

[89] R Barone G Bertrand J Simpore M Malaguarnera and SMusumeci ldquoPlasma chitotriosidase activity in 120573-thalassemiamajor a comparative study between Sicilian and SardinianpatientsrdquoClinica Chimica Acta vol 306 no 1-2 pp 91ndash96 2001

[90] A Acar M Keskek F K Isman M Kucur and M TezldquoSerum chitotriosidase activity in acute appendicitis prelimi-nary resultsrdquo American Journal of Emergency Medicine vol 30no 5 pp 775ndash777 2012

[91] J K H Brunner S Scholl-Burgi D Hossinger P WondrakM Prelog and L-B Zimmerhackl ldquoChitotriosidase activity injuvenile idiopathic arthritisrdquo Rheumatology International vol28 no 9 pp 949ndash950 2008

[92] M Kucur F K Isman C Balci et al ldquoSerum YKL-40 levelsand chitotriosidase activity as potential biomarkers in primaryprostate cancer and benign prostatic hyperplasiardquo UrologicOncology Seminars and Original Investigations vol 26 no 1pp 47ndash52 2008

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology