Role of Chemokines for the Localization of Leukocyte Subsets in the

Iicgiswrrmc[tM

MS

A

0©

2

Role of Chemokinesfor the Localization of

Leukocyte Subsets in the Kidney

Stephan Segerer, MD, and Detlef Schlöndorff, MD

Summary: Chemokines comprise a family of structurally related chemotactic proteins. Theybind to about 20 corresponding receptors. Chemokines provide a general communicationsystem for cells, and regulate lymphocyte migration under normal (homeostatic) and inflam-matory conditions. Chemokines organize microenvironments in lymphoid tissue, lymphoidorganogenesis, and participate in vascular and lymphatic angiogenesis. Expressed at the siteof injury in the kidney, chemokines are involved in the recruitment of specific leukocytesubsets to particular renal compartments. Here we summarize recent data on chemokinebiology with a focus on the role of chemokines in the recruitment of neutrophils (polymor-phonuclear leukocytes), monocytes/macrophages, dendritic cells, T cells, including regula-tory T cells, and B cells in renal inflammation.Semin Nephrol 27:260-274 © 2007 Elsevier Inc. All rights reserved.Keywords: Chemokines, glomerulonephritis, leukocyte recruitment, dendritic cells, macro-phages, B cells

CO

T

D(nktpkceencrtadetr

i

nflammation is a prerequisite for renal fibro-sis in all chronic human kidney diseases andin animal models.1 Chemokines are involved

n the recruitment of specific subsets of leuko-ytes to the injured kidney and to renal allo-rafts.2,3 Various aspects of chemokine biologyn renal diseases have been reviewed exten-ively by us and others.2-6 In the present reviewe use a cell-centered approach to describe

ecent developments in our understanding ofenal inflammation, focusing on the involve-ent of chemokines and in the recruitment of 5

ell types (ie, polymorphonuclear leukocytesPMNs], B cells, and T cells, including regula-ory T cells, monocytes/macrophages [Mo/ac], and dendritic cells [DCs]).

edizinische Poliklinik, University of Munich, Munich, Germany.upported in part by grants from the Else Kröner-Fresenius Stiftung (BadHomburg an der Höhe, Germany) and the Deutsche Forschungsgemeinschaft(SE 888/4-1).

ddress reprint requests to Stephan Segerer, MD, Medizinische Poliklinik, Petten-koferstr. 8a, 80336 Munich, Germany. E-mail: [email protected]

270-9295/07/$ - see front matter
c2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2007.02.003
Semina60

URRENT ASPECTSF CHEMOKINE BIOLOGY

he Chemokine Family

uring recent years the number of chemokinesL for ligand) and chemokine receptors (R) hasot increased significantly and, because of thenowledge of the human genome, little addi-ional identifications are expected. However,osttranscriptional modifications of chemo-ines and heterodimerization of chemokine re-eptors are increasingly recognized and consid-rably expand the spectrum of biologicalffects of the system.7,8 N terminal changes viaaturally occurring proteases significantlyhanges chemokine functions, with responsesanging from activation (eg, for CXCL7/NAP-2)o the biological active chemokine, increasedctivity (eg, for CXCL8/interleukin [IL]-8), toecreased activity (eg, for CXCL9/MIG), orven antagonistic function.8 Agonistic and an-agonistic functions of chemokines on differenteceptors also have been described.9,10

A motif of 4 conserved cysteine residuesn the primary structure is used to divide the
hemokines into 4 subgroups (CCL, CXCL,
rs in Nephrology, Vol 27, No 3, May 2007, pp 260-274

Conmbcto

C

Cspwakmfcfoinp

mrsdotsamasenattrokktt

C

Fi

soflCclsmltnfihmCFCcrcifpfcmbprrikcc(pcpepapDkltrmw

Chemokines in renal inflammation 261

X3CL1, and XCL1), according to the positionf the N terminal 2 cysteines and interveningonconserved amino acids (X).11,12 The N ter-inus of chemokines is important for receptor

inding and specificity, whereas areas in theore and the C terminus are important for ma-rix binding and presentation of the chemokinen the glycocalyx of the endothelial surface.13

hemokine Receptors

hemokine receptors are 7 transmembrane-panning proteins, coupled to heterotrimeric Groteins, and activate various intracellular path-ays such as small guanosine triphosphatases

nd kinases.12,14 It has been shown that chemo-ine receptors can cross-desensitize other che-okine receptors. Chemokine receptors can

orm homodimers and heterodimers.15,16 CChemokine receptor (CCR5), for example,orms heterodimers with CCR2b, and bindingf CCR5 ligands prevents CCL2/ MCP-1 signal-

ng.15 Therefore, paradoxically, chemokine ago-ists might be suitable anti-inflammatory thera-eutics under specific conditions.17

By binding to their respective receptors, che-okines fulfill major functions in leukocyte

ecruitment to the site of tissue injury.12 Pre-ented by glycosaminoglycans (GAGs) on the en-othelial surface, chemokines activate integrinsn rolling leukocytes. This transforms integrinso a high-affinity state, and mediates firm adhe-ion of the leukocyte to the endothelium, andllows their extravasation.18,19 Therefore, che-okines that activate integrins may be calledrrest chemokines.18 To mediate firm adhe-ion, chemokines need to be transported to thendothelial surface. The involvement of nonsig-aling chemokine receptors such as the duffyntigen/receptor for chemokines (DARC) inhis process is very likely.20-22 After having lefthe vasculature, chemokines mediate the di-ected migration of leukocytes toward the sitef injury, likely following matrix-bound chemo-ine gradients.23 A rapid change in the chemo-ine-receptor pattern enables leukocytes to ei-her remain tissue bound, to leave the tissue, oro interact with other cells.12

hemokine Function

unctionally, chemokines were labeled as
nflammatory or homeostatic, but there is g
ome overlap between the groups.12 The focusf the renal literature has been mostly on in-ammatory chemokines such as CCL2/MCP-1,CL5/RANTES, or CXCL10/IP-10.2,3,6,24-26 Thesehemokines are rapidly up-regulated and re-eased by proinflammatory cytokines and celltress at the sites of injury.3 Homeostatic che-okines are thought to be involved in cellular

ocalization, recirculation, and cell-cell interac-ions under noninflammatory conditions. Fi-ally, some chemokines (eg, CCL22/MDC) ful-ll both functions. Furthermore, there may beeterophilic interactions between chemokinesodifying their function (eg, CXCL4/PF4-XCL8/IL-8 and CXCL4/PF4-CCL5/RANTES).27

or example, CXCL4/PF4 together withXCL8/IL-8 inhibits rather than induces mono-yte arrest under flow conditions. Besides theecruitment and positioning of inflammatoryells to sites of injury, chemokines are involvedn the recruitment of leukocytes and stem cellsrom the bone marrow in vascular and lym-hatic angiogenesis and in tumor metastasis

ormation (via recruitment of tumor cells toertain organs). The multiple functions of che-okines and chemokine receptors are achieved

y a versatile and dynamic system. For exam-le, ligand binding to chemokine receptors canesult in rapid internalization of the chemokineeceptor, which stops cell movement. Concom-tantly the cells may express different chemo-ine receptors that enable response to otherhemotactic factors.28 Expression of the samehemokine receptor on 2 different cell typeseg, CCR7 on naive T cells and mature DCs)rovides for a rendezvous of these cells in spe-ific mircroenvironments.29 It has become ap-arent that the change of chemokine-receptorxpression during maturation or activationlays an important role in immune surveillancend that the picture is by far less static thanreviously expected. Monocytes and immatureCs express receptors for inflammatory chemo-ines (eg, CCR5, CCR2, and CCR1), which al-ows them to be recruited to the site of acuteissue injury.29 T-cell activation results in down-egulation of CCR7 and up-regulation of inflam-atory receptors such as CXCR3 and CCR5,hich allows them to leave the lymph node and

uide them toward the site of injury.29 On acti-

viursDdeDcvAmeTsrpmb

RI

TctispcrqbsvbIcgcos

swsrpaa

bpnlsrnpcmeAttbGwcCdcmCciwtdvtorpbdrl

Imtocf

tgPn

262 S. Segerer and D. Schlöndorff

ation and maturation of DCs the receptors fornflammatory chemokines are rapidly down-reg-lated, and others, particularly CCR7, are up-egulated. CCL21, the ligand for CCR7, is pre-ented by lymphatic endothelium, thereby MO/Cs can travel from the injured organs to theraining lymph nodes. Immature T cells alsoxpress CCR7, therefore the cells meet withCs in the lymph node–T-cell area.29 Similaroncepts currently are being developed for thearious cell partners of the immune system.nother example are B cells, which need toeet with T cells in lymphoid tissue. Here the

xpression of CXCR5 on B cells and specializedcells enables this copositioning.30 Recent data

how that the chemokine system not only mayegulate leukocyte movement between lym-hatic organs and sites of tissue injury, but alsoay govern leukocyte mobilization from the

one marrow to the periphery.31

OLE OF CHEMOKINESN THE RECRUITMENT OF PMNS

he CXC chemokine CXCL8/IL-8, binding to itsorresponding receptors (ie, CXCR1/2), washe first neutrophil-selective chemoattractantdentified.12,32-34 Initially CXCL8/IL-8 was de-cribed as being released by monocytes/macro-hages, an observation that may be of signifi-ance for the early as well as late PMNecruitment noted in many diseases.35 Subse-uently, many cell types have been reported toe able to generate CXCL8/IL-8 in culture whentimulated with proinflammatory factors (re-iewed in Segerer et al3). Besides the inductiony typical proinflammatory cytokines, CXCL8/L-8 also has been reported to be induced inultured tubular epithelial cells by transformingrowth factor-� 136 and by exposure to highoncentrations of albumin.37 The significancef these in vitro observations for the in vivoituation remains to be determined.

The functional role of CXCL8/IL-8 has beentudied in animal models of renal diseases asell as in patients. Early studies by Wada et al38

howed decreased proteinuria and neutrophilecruitment in rabbits with an immune com-lex nephritis treated with an anti–CXCL8/IL-8ntibody. In patients with glomerular diseases
n increased urinary CXCL8/IL-8 excretion has k
een shown in various forms of glomerulone-hritis (GN), including immunoglobulin A (IgA)ephropathy, membrano-proliferative glomeru-

onephritis (MPGN), and lupus nephritis.39 Wetudied the expression of the correspondingeceptor CXCR1 in glomerular diseases.40 Inormal renal tissue CXCR1 protein was ex-ressed by a low number of circulating leuko-ytes and intrinsic renal cells, including smoothuscle cells of small arteries and arterioles,

ndothelial cells, and, occasionally, podocytes.prominent number of CXCR1-positive infil-

rating cells were found both in glomeruli andhe tubulointerstitium with the highest num-ers in MPGN, lupus nephritis, and crescenticN.40 The CXCR1-positive infiltrating cellsere predominantly PMNs according to the nu-

lear morphology and consecutive staining forD15 (a neutrophil marker). Furthermore, theistribution and cell number of CXCR1-positiveells was distinct from that of CD68-positiveonocytes/macrophages. Thus, a prominentXCR1-positive PMN infiltrate was found inhronic glomerular diseases, with a strong co-nfiltrate of macrophages. These data point to-

ard an ongoing recruitment of CXCR1-posi-ive PMNs in the course of chronic renaliseases. This is contrary to the widely heldiew that PMNs only contribute to the induc-ion of the inflammatory processes. In a modelf lung inflammation, it was shown that earlyecruitment and activation of Mo/Mac was arerequisite for PMN recruitment.41 This woulde consistent with CXCL8/IL-8 generation pre-ominantly by Mo/Mac. This would indicate aole for CXCL8/IL-8, CXCR1, and PMNs also inater phases of the inflammatory process.

In a study on human renal allografts, CXCL8/L-8 expression was increased significantly 30inutes after declamping of the arterial graft anas-

omosis.42 CXCL8/IL-8 expression increased bynly 50% in living donor grafts, but by 13-fold inadaver donor grafts, indicating an important roleor ischemia in attracting PMNs.42

Furthermore, recent studies have indicated in-eractions of PMNs with DCs, potentially as dan-er sensors and for DC maturation. Therefore,MNs might potentially act as links between in-ate and adaptive immune responses in chronic
idney diseases and in renal allografts.43

RIM

TkmDaprpDsFpmvidhdptsatoCtsa

sRCacm

bifatCCIwam

a(tC

iictmcfAdM

miCTh(attkMtzcnnhkbCtacCcjBosaMpC


OLE OF CHEMOKINESN THE RECRUITMENT OF

O/MAC IN RENAL INFLAMMATION

he distinction between Mac and DCs in theidney, both in health and disease, is becomingore fluent than previously thought.44 Mac andCs are part of the mononuclear phagocyte andntigen presenting system. As such, they playivotal roles in innate and adaptive immuneesponses.45,46 It is increasingly becoming ap-arent that the development of Mo/Mac andCs is a very dynamic process and that no

ingle cell marker can be assigned to these cells.unctionally, Mac can be activated to varioushenotypes, ranging from the classic cytotoxicacrophage to an anti-inflammatory cell in-

olved in tissue remodeling.46 The heterogenic-ty of Mo/Macs reflects plasticity rather thenefined lineages because a common progenitoras been described in mice.45-48 For a detailediscussion of the various monocyte activationathways see Mantovani et al.48 In brief, Moreated in vitro with proinflammatory cytokinesuch as tumor necrosis factor-� and interferon-�dopt a classic activated phenotype and releaseoxic mediators (eg, nitric oxide and reactivexygen intermediates). Chemokines such asCL2/MCP-1 can additionally increase the cyto-

oxicity of these cells.46 The other end of thepectrum of macrophage activation results inlternatively activated cells.48

The classically activated macrophagehowed a stronger expression of messengerNA for CCR7, as well as the chemokinesCL5, CCL19, CXCL 9-11, as compared withlternatively activated macrophages in vitro,haracterized by low production of proinflam-atory cytokines.49

In the mouse, 2 monocyte populations haveeen described in the peripheral blood.50 One

s short lived, expresses low amounts of theractalkine receptor (CX3CR1), but highmounts of CCR2, and is recruited to inflamedissue.50 The other cell type does not expressCR2 and localizes to noninflamed tissue viaX3CR1.50 Both cell types can give rise to DCs.

n human beings these 2 monocyte populationsere described as CX3CR1lowCD14(�)CD16(�)

nd CD14lowCD16�, respectively.50 Further-
ore, freshly isolated blood monocytes express e
panel of inflammatory chemokine receptorsCCR1, CCR2, and CCR5).48 Differentiation intoissue macrophages is associated with a loss ofCR2, but induction of CCR1 and CCR5.48

In the kidney, Mo/Mac are the most commonnflammatory cells in glomeruli with proliferat-ng GN, and together with T cells are the mostommon infiltrating cell types in the diseasedubulointerstitium.46 There are 2 sources foracrophages in inflamed kidneys, those re-

ruited from the circulation and those derivedrom proliferation of resident monocytic cells.t present their relative contributions are notefined, but the proliferation of intrarenal Mo/ac may have been underestimated to date.46

Currently the most commonly described che-okines for Mo/Mac recruitment during renal

nflammation are CCL2/MCP-1, CCL5/RANTES,CL3/MIP-1�, CCL4/MIP-1�, and CXCL8/IL-8.he corresponding receptors mediate firm ad-esion (CCR1 and CXCR2), and shape changeCCR2 and CCR5), spreading (CCR2, CCR5),nd transmigration.46,51 Once Mo/Mac haveransmigrated into the interstitium they appearo change their surface expression of chemo-ine receptors (eg, loss of CCR2). Migration ofac through the interstitial tissue is facilitated

hrough the release of matrix degradative en-ymes by the Mac, which is mediated in part byhemokines.46 Various models (eg, nephrotoxicephritis, unilateral ureter ligation, adriamycinephropathy, and models of lupus nephritis)ave been studied for the expression of chemo-ines and the potential benefits of chemokinelockade. In general, chemokines such asCL2/MCP-1, CCL5/RANTES, and CX3CL1/frac-

alkine were found to be expressed in the dam-ged renal compartment and preceded the re-ruitment of inflammatory cells. Blockade ofCL2/MCP-1 and CX3CL1/fractalkine signifi-antly improved glomerular and interstitial in-ury and reduced Mo/Mac recruitment.52-54

lockade of CCR1 using a small molecule antag-nist prevented Mo/Mac recruitment and inter-titial fibrosis in UUO and adriamycin nephrop-thy.55,56 Detailed studies on the roles of CCL2/CP-1 and the receptor CCR2 have beenerformed in lupus models. The blockade ofCL2/MCP-1 function or genetic deficiency of
ither the ligand CCL2 or the receptor CCR2

rfmiatTfrcttl

CI

TtdtilsrimggiiwsmpCIBCB

rfDwitpiis

tltdtitdtmcCttnaecDrtlCpaacngowo

tcctmflDumcmspk8M


esulted in decreased Mo/Mac recruitment andunctional improvement in lupus nephritisodels.57-59 On the other hand, exacerbation of

nflammatory models in CCR2-deficient micend in mice treated with N-terminal modifica-ions of CCL5 also have been described.60,61

he reasons for these apparently opposing ef-ects remain unclear at present but may beelated to other immune functions of the spe-ific chemokines during the development ofhe renal disease models. Detailed reviews ofhe available animal studies have been pub-ished recently.2,3,5

HEMOKINES AND DCSN RENAL INFLAMMATION

he realization that the development and rela-ion between Mo/Mac and DCs is much moreynamic than previously thought also applies tohe kidney. DCs have a high phagocytic activityn an immature state, and accumulate costimu-atory molecules to induce strong T-cell re-ponses during maturation. DCs play a centralole in the induction and regulation of adaptivemmune responses, controlling B and T cells as

ediators of immunity.62 In vitro DCs can beenerated from myeloid and plasmacytoid pro-enitors (showing different migration behav-or). Furthermore, the DC subsets differ accord-ng to the lymphoid or nonlymphoid organ

here they reside.63 For example, in the mousepleen 4 DC subsets have been characterized: 2yeloid DCs (major histocompatibility com-lex [MHC] II low, CD11c�, CD11b�,D205�, CD8��, B220�), 1 lymphoid (MHC

I low, CD11c�, CD11b�, CD205�, CD8��,220�), and 1 plasmacytoid (MHC II low,D11c�, CD11b�, CD205�, CD8��, CD4 �,220�, Gr1�).For the kidney we will refer to Mac/DC cells

ather than DC only because there are fluidunctions and definitions between Mac andCs. The kidney contains an interstitial net-ork of cells that previously were labeled as

nterstitial cells, or resident monocytes.64 Inhe mouse kidney these F4/80� cells may inart represent a DC network, performing an

ntrarenal surveillance role. Such DCs residen most tissues under normal conditions and
ense danger signals.65 After activation some of C
hese DCs travel from the tissue to the drainingymph node, whereas others remain and poten-ially proliferate locally. In these processes theifferent Mac/DCs change their phenotype, sohat by surface markers different types can bedentified. At present it remains unclear if thisruly represents differentiation of Mac/DCs orifferent stages of a dynamic cell function. Inerms of chemokine-receptor expression, im-ature DCs express receptors for inflammatory

hemokines (CCR1, CCR2, CCR4, CCR5, andXCR3), which allow them to migrate toward

he site of injury.66 During maturation mediatedhrough a variety of factors (eg, IL-1, tumorecrosis factor, and lipopolysaccharide), DCscquire costimulatory potential and MHC mol-cules. This is associated with a functionalhange in the chemokine-receptor pattern.own-regulation of inflammatory chemokine

eceptors and induction of CCR7 allows themo leave the site of injury and migrate towardymphatic vessels. The corresponding ligandCL21/SLC is expressed and presented by lym-hatic endothelial cells.66 Mature DCs, whichre characterized by less phagocytic activitynd a strong expression of costimulatory mole-ules, find their way into the draining lymphodes where they interact with T cells in anti-en presentation and T-cell activation. On thether hand, DCs also can have tolerizing effectshen they express autoantigens in the absencef costimulatory molecules.

It should be apparent from this brief descrip-ion that, similar to the development of mono-ytes to macrophages, the macrophage to DChanges are highly dynamic, so that it is difficulto put the cells into specific categories. Further-ore, the transition from Mo/Mac to DCs is a

uent one. Because unique markers specific forCs do not exist, DCs may have been describednder various labels in the kidney. In the nor-al mouse kidney a network of F4/80-positive

ells in the tubulointerstitium was describedore than 20 years ago.64 Kruger et al67 de-

cribed a population of CD11c and MHC II–ositive cells with DC functionality in mouseidneys. Most of these cells also expressed F4/0. Others have taken advantage of the fact thatac/DCs express the fractalkine receptor
X3CR1 constitutively, which mediates their

licwiflCflpoBMctCwcgpismttbmsDldWmcgtLwfciSlppCptrao

kiCbosonbeosaci

CA

BaftBlctecmmlcTg

iTsgpaimBoaFa


ocalization to nonlymphoid tissue under non-nflammatory conditions.68,69 Soos et al70 re-ently described an interstitial network of cellsith dendritic morphology and CX3RCR1 pos-

tivity in kidneys of mice transgenic for greenuorescence protein under control of theX3CR1 promoter. By fluorescence-activatedow cytometry the green fluorescence protein–ositive cell population showed co-expressionf CD11c, and was F4/80low, CD4�, CD8��,220�, and Gr-1negative, with high expressionHC II, consistent with myeloid DCs.70 These

ells showed immature costimulatory compe-ence (low expression of CD80, CD86, andD40), but strong phagocytic ability.70 Thisould be consistent with immature DCs and

losely resembles interstitial DCs in other or-ans (eg, the lung). Clearly, evidence for a cellopulation with DC morphology and function

s evolving in the mouse kidney. Because aignificant part of these cells also expressed thearker F4/80, which is a common marker used

o describe macrophages, the distinction be-ween monocytes/macrophages and DCs hasecome blurry. Although these Mac/DC cellarkers have been described for the mouse

ystem, the expression of cell antigens by Mac/Cs in the human kidney are not well estab-

ished. Kerjaschki71 used the marker S100 toescribe a DC population in human allografts.e recently compared CD68 (a marker com-only used for human Mo/Mac), dendritic

ell-specific intercellular-adhesion-molecule-rabbing non-integrin (DC-SIGN) (for imma-ure DCs), S100, and langerin (a marker ofangerhans cells) in renal biopsy specimensith various forms of glomerulonephritis. We

ound a strong recruitment of CD68-positiveells to glomeruli and the tubulointerstitiumn proliferative GN. A high number of DC-IGN–positive cells were present in the tubu-ointerstitium (some cells being CD68 doubleositive), but no DC-SIGN expression wasresent in glomeruli. This indicates thatD68-positive cells differ in the 2 renal com-artments (ie, glomerular and tubulointersti-ial). Mature DCs identified by S100 or lange-in were detectable but rare in both normalnd inflamed kidneys (Segerer, unpublished
bservation). s
Studies in vitro and in organs other thanidney have indicated that CCR7 and variousnflammatory chemokine receptors (eg,XCR3, CCR1, CCR5, and so forth) also mighte involved in the recruitment and positioningf these cells.72 It will be a major task for futuretudies to describe the localization and functionf the various Mac/DC types in the human kid-ey and the expression of chemokine receptorsy these cells, as well as the cytokine patternxpressed by these cells. The resident networkf Mac/DCs in the kidney may perform a con-tant surveillance function and may after insultlso serve as an early and major source forytokines (perhaps including chemokines) dur-ng tissue injury.73

HEMOKINES, B CELLS,ND RENAL INFLAMMATION

cells function as effector cells primarily viantigen-specific expansion and plasma-cell dif-erentiation. The renal literature has focused onheir role as antibody-producing cells, whereascells infiltrating the kidney have received very

ittle attention. B cells can release a variety ofytokines (including chemokines), present an-igens, and are involved in lymphangioneogen-sis and lymphoneogenesis.74-76 A role for Bells in tissue fibrosis has been shown in aodel of CCl4-induced liver injury. In thisodel about half of the infiltrating cells in the

iver were found to be B cells, and B-cell defi-iency significantly improved liver injury.77

his improvement was not T-cell or immuno-lobulin dependent.77

Most B-cell responses to antigens need thenvolvement of DCs and antigen-specific-helper cells. T-cell–dependent responses re-ult in short-lived plasma cell differentiation anderminal center development of long-livedlasma cells and B memory cells.78 Chemokinesre involved in the positioning of the interact-ng cell types in lymphatic microenviron-

ents.79 Recirculating naive B cells localize to-cell follicles in secondary lymphoid organswing to the expression of CXCR5 on B cellsnd CXCL13/BLC by follicular stromal cells.80,81

urthermore, naive B cells express moderatemounts of CCR7. Having encountered their
pecific antigen, B cells rapidly relocalize to the

BarbCspgbh

bcosrosnaicwm

ttICoptaCatmCCBfsm

C

Cmtdt

p(cpCccmwvTeCwCcceibc

pTapgTficgTCbntCtt(

thFCC

a


-/T-cell boundary area. This is associated withrapid induction of CCR7, whereas CXCR5

emains expressed.82 The expression of CCR7y B cells and T cells enables them to meet. TheXCL13/BLC and CXCR5 knockout mice wereeverely deficient in lymph nodes and Peyer’satches, indicating a role during lymph-organo-enesis.30,83 Furthermore, CXCL13/BLC haseen shown to act as an arrest chemokine onigh endothelial venules.84,85

B cells accumulating in renal allografts haveeen shown to be associated with a poor out-ome.86 Steinmetz et al87 studied serial sectionsf 23 allograft biopsy specimens for the expres-ion of CD20, CXCR5, and CXCL13/BLC. Acuteejection was found in 13 biopsy specimens, 4f which contained clusters of B cells. Biopsypecimens with acute rejection showed a sig-ificantly increased expression of CXCL13/BLCs compared with nonrejecting allografts. Bymmunohistochemistry, sites of CXCR5-positiveells correlated with CXCL13/BLC, and bothere restricted to sites of nodular B-cell accu-ulation.87

We studied renal biopsy specimens from pa-ients with acute and chronic primary intersti-ial nephritis, and from patients with chronicgA nephropathy and interstitial involvement.88

D20-positive B cells formed a prominent partf the interstitial infiltrates and formed lym-hoid-like nodular structures in about a third ofhe biopsy specimens. These infiltrates weressociated with expression of CXCL13/BLC andXCR5 (consistent with the data shown forllografts). These data indicate that B-cell infil-rates appear to play a role during renal inflam-ation that was not previously appreciated.XCL13/BLC and the corresponding receptorXCR5 likely are involved in the recruitment ofcells to the kidney, particularly to lymphoid

ollicle-like structures. These tertiary lymphoidtructures could be a site of an intrarenal im-une response.

HEMOKINES AND T CELLS

hemokines play crucial roles during early thy-ocyte development, positioning, T-cell selec-

ion, and central memory.89 Self-tolerance is me-iated by deletion of self-reactive cells in the
hymus. T cells need to meet with antigen- c
resenting cells in T-cell areas to be activatedsee previously). During maturation, T cellshange the pattern of chemokine-receptor ex-ression from constitutive receptors such asCR7, to a receptor pattern for inflammatoryhemokines such as CXCR3 and CCR5.29 Thehemokine CXCL10/IP-10 has been shown toediate a T-helper type I (TH1) response,hereas CCL2/MCP1 and CXCL4/PF-4 are in-

olved in TH2 responses.90 The different-helper cell types also are reflected by differ-nt chemokine-receptor expression. CCR4 andCR8 are expressed mainly by TH2 cells,hereas TH1 cells express predominantlyCR5 and CXCR3. A third subset of T effectorells (ie, TH17 cells) has been described re-ently, which is involved in protection againstxtracellular bacteria as well as in various auto-mmune diseases.91,92 These cells express IL-17,ut the chemokine-receptor pattern of theseells has not been described so far.

In the periphery, self-tolerance is mediated inart by a group of special T cells (ie, regulatorycells [Tregs]). These cells actively suppress

utoreactive T cells.93 A role of Tregs in variousathologies such as autoimmune disease, allo-raft injury, and so forth, is evolving rapidly.regs express CD4, CD25, and the transcription

actor FOXP3.93 Human CD4-CD25 double-pos-tive Tregs have been shown to express thehemokine receptors CCR4 and CCR8, and mi-rate toward the corresponding ligands CCL17/ARC and CCL1/I-309.94,95 Migration towardCL22/MDC, another ligand of CCR4, also haseen described. In human bone marrow a highumber of Tregs has been described, whichraffic via CXCL12/SDF-1 as a ligand forXCR4.96 A recent study showed a change in

he chemokine-receptor pattern during activa-ion of Tregs from a lymphoid-homing patternCCR7) to a tissue-homing pattern.97

In the mouse, CD25-positive Tregs respondo CCL4 via the receptor CCR5.98 In a mouseeart allograft model, the recruitment ofOXP3-positive T cells also was related toCL17/TARC and the corresponding receptorCR4.99

Inflammatory cells, such as activated B cellsnd mature DCs, might be the source of the
hemokine CCL17/TARC attracting Tregs.100

TaCt

arriaCmdSp

sTwpboflw

samllrFhatcw

C

FiTrlelmpb

assbsCfitttgppbatomdrorcfitdihldaatltbaaut

RI

BmCcbC


regs interact directly with effector T cells andntigen presenting cells (APC), and thereforeCR4, CCR5, and CCR8 might be involved in

his rendezvous.Mahajan et al101 recently showed that Tregs

meliorated responses of macrophages in vitro,esulting in down-regulation of CCL3/MIP-1�elease by macrophages. These investigators101

nduced adriamycin nephropathy in scid micend reconstituted them with FOXP3-positiveD4/CD25-positive cells. Tregs reduced glo-erular and tubulointerstitial injury, with re-

uced numbers of infiltrating macrophages.101

imilarly, FOXP3-transduced T cells showed arotective effect in this model.102

Muthukumar et al103 measured FOXP3 mes-enger RNA in the urine of allograft recipients.hirty-six subjects with acute rejection and 18ith chronic allograft nephropathy were com-ared with 29 subjects with normal transplantiopsy specimens. A significantly higher levelf FOXP3 messenger RNA expression wasound during acute rejection, but was corre-ated inversely with serum-creatinine level and

ith graft loss at 6 month.103

These results indicate that part of the inter-titial infiltrate, especially Tregs, and potentiallylso DCs, may have regulatory properties andight be of positive prognostic impact. It is

ikely that ongoing studies will shed furtheright on the role of regulatory cells in mouseenal models and in human kidney diseases.urthermore, some of the negative effects thatave been described for chemokine blockinggents might relate to the blockade of regula-ory cells. Obviously this adds another layer ofomplexity to the interaction of chemokinesith various types of leukocytes.

HEMOKINES AND FIBROCYTES

ibrocytes are bone marrow–derived circulat-ng cells with fibroblast-like properties.104

hese cells initially were described in woundepair, but also play important roles in granu-oma formation and in fibrosing diseases of sev-ral organs.105 Fibrocytes express vimentin, col-agens I and III, CD34, and produce matrix

etalloproteinases.105 By bone marrow trans-lantation experiments it has been shown that
one marrow–derived donor cells accumulated e
t the site of granulation tissue. These cellsubstantially contributed to collagen expres-ion at the site of injury and expressed fibro-last specific protein-1.106 In pulmonary fibro-is, recruitment of fibrocytes was mediated byXCR4 and CCR2.107,108 Furthermore, in vitrobrocytes migrate to CCL21/SLC, a ligand forhe receptor CCR7.109 In a very recent publica-ion on a mouse model of unilateral ureter liga-ion, cells double positive for CD34 and colla-en I were recruited to the kidney at least inart via CCR7.110 These cells were mostly CCR7ositive and blocking CCL21/SLC by an anti-ody or deficiency of CCR7 reduced fibrosisnd the infiltration of fibrocytes. In addition,he number of macrophages and the expressionf CCL2/MCP-1 was reduced.110 Therefore, che-okine-mediated recruitment of bone marrow–

erived fibrocytes into injured tissue may rep-esent a hitherto underestimated mechanism ofrgan fibrosis, including in the kidney. Thisapidly developing field most likely will haveonsiderable impact on our understanding ofbrosing diseases and their therapy. In this con-ext the observation may be of interest thateficiency of the von Hippel-Lindau (VHL) gene

n podocytes of mice leads to overexpression ofypoxia-inducible factor (HIF)-regulated vascu-

ar endothelial growth factor (VEGF) and theevelopment of a crescentic GN. The prolifer-ting cells in crescents were CXCR4 positivend a blocking antibody for CXCR4 preventedhe crescentic GN.111 If this relates to the pro-iferation of CXCR4-positive podocytes or po-entially CXCR4-positive stem cells or even fi-rocytes (see later) remains to be evaluated. Inny case, fibrocytes constitute an interestingnd hitherto probably underestimated cell pop-lation that potentially may become therapeu-ic targets during progressive renal fibrosis.

OLE OF CHEMOKINESN STEM CELL RECRUITMENT

ecause in-depth discussion of stem cell recruit-ent is beyond the scope of this article,XCL12/SDF-1 is considered to mobilize stemells via CXCR4. CXCL8 has been reported toe expressed in the normal mouse kidney.112

XCL12/SDF-1 expression increased after isch-
mia-reperfusion in the kidney, but decreased

iocvcii

RRD

E(dFctatpadttptauHtatmpdtlcssor

upvriCs

spaMtpGab

wftsalHglwRseCwwmrbisbfk

DckbIoroflpcDwT


n the bone marrow. This caused mobilizationf CD34-CXCR4 double-positive cells into theirculation and their homing to the kidney. Initro and in vivo chemotaxis of bone marrowells toward damaged kidney epithelium wasnhibited reversibly by anti-CXCR4 antibod-es.112

OLE OF CHEMOKINES FOR THEECRUITMENT OF LEUKOCYTES TOIFFERENT RENAL COMPARTMENTS

vidence is increasing that renal compartmentsie, glomerular and tubulointerstitial capillaries)iffer in the recruitment of inflammatory cells.or example, PMNs and Mo/Mac can be re-ruited to both the glomerular tufts and theubulointerstitial compartment. By contrast, Tnd B cells almost exclusively are recruited tohe tubulointerstitium even in glomerulone-hritis. Especially T cells frequently conglomer-te around Bowman’s capsules. This differentialistribution of leukocyte subsets is reflected byhe respective expression of chemokine recep-ors. For example, CCR5 and CXCR3 are ex-ressed mainly by T cells in the tubulointersti-ium.113,114 In contrast, CXCR1-positive PMNsnd CCR2-positive Mo/Mac are found in glomer-lar tufts and in the tubulointerstitium,40,115

owever, macrophages in glomeruli and theubulointerstitium may be in a different state ofctivation or maturation because they differ inhe expression of markers. For example, inice interstitial but not glomerular macro-hages express the F4/80 antigen (see also theiscussion on DCs previously).116 The differen-ial recruitment of the various leukocyte popu-ations to the glomerular and tubulointerstitialompartment could involve differences in sheartress, chemokine expression, chemokine pre-entation on the endothelium, and expressionf adhesion molecules. We briefly discuss theole of chemokines here.

Although all intrinsic renal cells can be stim-lated to release chemokines in vitro, a com-artment-specific expression of chemokines inivo has been described in 2 studies.117,118 In aat model of renal microvascular endothelialnjury, the expression of the chemokineXCL10/IP-10 was restricted to the tubulointer-
titium, although the glomerular capillaries also i
howed severe injury. The tubulointerstitial ex-ression of CXCL10/IP-10 correlated with T-cellccumulation in this compartment. CCL2/CP-1 was expressed both in glomeruli and in

he tubulointerstitium, consistent with macro-hage recruitment to both compartments.118 Inoldblatt hypertensive rats the CXCR3 ligandslso were expressed predominantly in the tu-ulointerstitium.117

Chemokines are thought to function in vivohen presented by GAG structures on cell sur-

aces or extracellular matrix.119,120 The presen-ation of chemokines on GAGs facilitates adhe-ion and migration under flow and potentiallylso by haptotaxis (ie, migration along extracel-ular matrix–bound chemokines) in tissues.eparin sulphated GAGs may be different inlomeruli and on endothelial cells of peritubu-ar capillaries. By using an in situ binding assay

e recently showed that binding of CCL5/ANTES protein to normal renal tissue is re-tricted mainly to the tubulointerstitium, at thexclusion of glomerular structures. However,CL5/RANTES binding to the glomerular tuftas found in renal allograft biopsy specimensith acute transplant glomerulitis. Acute glo-erulitis in transplants, in contrast to other

enal diseases, is characterized by a high num-er of T cells in glomeruli. Therefore, these data

ndicate that differences in chemokine bindingtructures between renal compartments mighte important for compartmentalization of dif-erent leukocyte subsets infiltrating diseasedidneys.121

Nonsignaling chemokine receptors such asARC and D6 also might be involved in theompartment-specific presentation of chemo-ines. The chemokine binding protein DARCinds various chemokines including CXCL8/L-8 and RANTES/CCL5.122 DARC is expressedn peritubular capillaries, the site of leukocyteecruitment to the tubulointerstitium, but notn glomerular capillaries.123,124 During renal in-ammation including crescentic glomerulone-hritis, and allograft rejection (interstitial, vas-ular, and humoral), the number of interstitialARC-positive vessels increases in associationith recruitment of CCR5-positive T cells.123,124

he role of an increased number of DARC-pos-
tive peritubular capillaries currently is un-

klCpt

O

Ciihplad

p

epTmdhCotstptlel

FoCAr all pr


nown, but the restricted expression in the tubu-ointerstitium and the positive association withCR5-positive T cells in the corresponding com-artment suggests a role for transcytosis/presen-ation by DARC on specific endothelial cells.22

UTLOOK

hronic kidney diseases can result in a smolder-ng interstitial inflammatory response, contribut-ng to progression of diseases (Fig. 1). Here weave summarized data on the chemokine systemertaining to the infiltration and activity of several

eukocyte types (ie, PMNs, Mo/Mac, DCs, B cellsnd T cells including Tregs, and bone marrow–erived fibrocytes and stem cells).

In the human kidney recruitment of CXCR1-

igure 1. Progression phase in chronic kidney diseasesf leukocytes. The interstitial infiltrate contains CXCR1-pCR5-positive T cells. B cells form lymphoid-like structivation of tubular epithelial cells by proteinuria or iscelease, and secretion of chemokines by infiltrating cells

ositive PMNs to glomeruli and the tubuloint- n

rstitium has been shown in chronic diseases,articularly MPGN, lupus, and crescentic GN.hese cells might be recruited via signals ofacrophages and might interact with DCs as

anger sensors. At corresponding sites Mo/Macave been shown to express CCR2 andX3CR1. The expression of CX3CR1 on DCs inther organs and in the mouse kidney has madehis receptor a very interesting target for futuretudies. Little is known about B cells infiltratinghe kidney, but B cells account for a significantart of the renal interstitial infiltrates. B cellsogether with T cells and Mac/DCs can formymphoid-like follicles in chronic interstitial dis-ase, including renal allografts. CXCR5 and theigand CXCL13/BLC may recruit B cells to these

inflammatory milieu results in an ongoing recruitmente PMN, CCR2-positive macrophages, and CXCR3- and, including Mac/DCs, T cells, and lymphatic vessels., release of growth factors inducing further chemokineopagate ongoing interstitial inflammation.

. A proositiv

ctureshemia

odular infiltrates. Interstitial T cells express

tabaao

soflicagioimip[k

eccbCiCmTcfldcwm

R


he chemokine receptors CXCR3 and CCR5,nd correlate with renal function at the time ofiopsy. It is currently unclear which percent-ge of T cells bare Treg markers, and mightctually be of positive impact for the resolutionf the disease.

It is likely that the chronic inflammatory re-ponse is mediated through amplification loopsf the system. Involved in the permanent in-ammatory process might be proteinuria, caus-

ng chemokine induction in tubular epithelialells or activation of DCs, and ischemia second-ry to rarefaction of the microvasculature witheneration of proinflammatory cytokines result-ng in further chemokine expression. In favorf a contributing role of the chemokine system

n these processes are the observations thatost of the factors that reduce or even reverse

nterstitial fibrosis (eg, bone morphogeneticrotein [BMP]-7, hepatocyte growth factorHGF]) also reduce the expression of chemo-ines and interstitial inflammatory infiltrates.

Finally, novel roles for chemokines still aremerging. For example, CCL2/MCP-1 and CCR2an be involved in the recruitment of mono-ytes into the peripheral circulation from theone marrow during infection.31 Furthermore,CR5-deficient mice show an increased humoral

mmune response in transplant models,125 andXCR3 and CCR7 may be involved in the recruit-ent of fibrocytes and regulatory T cells.110,126

herefore, the picture has become increasinglyomplex, with both proinflammatory, anti-in-ammatory, and antifibrotic roles evolving forifferent chemokines. These new aspects ofhemokine biology will have to be consideredhen interpreting studies with genetic or phar-acologic manipulation of chemokines.

EFERENCES1. Strutz F, Neilson EG. New insights into mechanisms

of fibrosis in immune renal injury. Springer SeminImmunopathol. 2003;24:459-76.

2. Segerer S, Nelson PJ. Chemokines in renal diseases.ScientificWorld J. 2005;5:835-44.

3. Segerer S, Nelson PJ, Schlondorff D. Chemokines,chemokine receptors, and renal disease: from basicscience to pathophysiologic and therapeutic studies.J Am Soc Nephrol. 2000;11:152-76.

4. Anders HJ, Ninichuk V, Schlondorff D. Progression
of kidney disease: blocking leukocyte recruitment
with chemokine receptor CCR1 antagonists. KidneyInt. 2006;69:29-32.

5. Panzer U, Steinmetz OM, Stahl RA, Wolf G. Kidneydiseases and chemokines. Curr Drug Targets. 2006;7:65-80.

6. Segerer S, Alpers CE. Chemokines and chemokinereceptors in renal pathology. Curr Opin NephrolHypertens. 2003;12:243-9.

7. Springael JY, Urizar E, Parmentier M. Dimerization ofchemokine receptors and its functional conse-quences. Cytokine Growth Factor Rev. 2005;16:611-23.

8. Proost P, Struyf S, Van Damme J. Natural post-trans-lational modifications of chemokines. Biochem SocTrans. 2006;34:997-1001.

9. Petkovic V, Moghini C, Paoletti S, Uguccioni M,Gerber B. I-TAC/CXCL11 is a natural antagonist forCCR5. J Leukoc Biol. 2004;76:701-8.

10. Proost P, Struyf S, Couvreur M, Lenaerts JP, ConingsR, Menten P, et al. Posttranslational modificationsaffect the activity of the human monocyte chemo-tactic proteins MCP-1 and MCP-2: identification ofMCP- 2(6-76) as a natural chemokine inhibitor. J Im-munol. 1998;160:4034-41.

11. Murphy PM. International Union of Pharmacology.XXX. Update on chemokine receptor nomenclature.Pharmacol Rev. 2002;54:227-9.

12. Murphy PM, Baggiolini M, Charo IF, Hebert CA,Horuk R, Matsushima K, et al. International union ofpharmacology. XXII. Nomenclature for chemokinereceptors. Pharmacol Rev. 2000;52:145-76.

13. Middleton J, Patterson AM, Gardner L, Schmutz C,Ashton BA. Leukocyte extravasation: chemokinetransport and presentation by the endothelium.Blood. 2002;100:3853-60.

14. Terricabras E, Benjamim C, Godessart N. Drug dis-covery and chemokine receptor antagonists: eppursi muove! Autoimmun Rev. 2004;3:550-6.

15. El-Asmar L, Springael JY, Ballet S, Andrieu EU, Vas-sart G, Parmentier M. Evidence for negative bindingcooperativity within CCR5-CCR2b heterodimers.Mol Pharmacol. 2005;67:460-9.

16. Springael JY, Le Minh PN, Urizar E, Costagliola S,Vassart G, Parmentier M. Allosteric modulation ofbinding properties between units of chemokine re-ceptor homo- and hetero-oligomers. Mol Pharmacol.2006;69:1652-61.

17. Ali S, O’Boyle G, Mellor P, Kirby JA. An apparentparadox: chemokine receptor agonists can be usedfor anti-inflammatory therapy. Mol Immunol. 2007;44:1477-82.

18. Ley K. Arrest chemokines. Microcirculation. 2003;10:289-95.

19. Baggiolini M. Chemokines and leukocyte traffic. Na-ture. 1998;392:565-8.

20. Rot A. Contribution of Duffy antigen to chemokinefunction. Cytokine Growth Factor Rev. 2005;16:687-94.

21. Rot A, von Andrian UH. Chemokines in innate and


adaptive host defense: basic chemokinese grammarfor immune cells. Annu Rev Immunol. 2004;22:891-928.

22. Pruenster M, Rot A. Throwing light on DARC. Bio-chem Soc Trans. 2006;34:1005-8.

23. Wiedermann CJ, Kowald E, Reinisch N, Kaehler CM,von Luettichau I, Pattison JM, et al. Monocyte hap-totaxis induced by the RANTES chemokine. CurrBiol. 1993;3:735-9.

24. Banas B, Wornle M, Merkle M, Gonzalez-Rubio M,Schmid H, Kretzler M, et al. Binding of the chemo-kine SLC/CCL21 to its receptor CCR7 increases ad-hesive properties of human mesangial cells. KidneyInt. 2004;66:2256-63.

25. Wornle M, Schmid H, Merkle M, Banas B. Effects ofchemokines on proliferation and apoptosis of hu-man mesangial cells. BMC Nephrol. 2004;5:8.

26. Banas B, Wornle M, Berger T, Nelson PJ, Cohen CD,Kretzler M, et al. Roles of SLC/CCL21 and CCR7 inhuman kidney for mesangial proliferation, migra-tion, apoptosis, and tissue homeostasis. J Immunol.2002;168:4301-7.

27. Weber C, Koenen RR. Fine-tuning leukocyte re-sponses: towards a chemokine ‘interactome’. TrendsImmunol. 2006;27:268-73.

28. Mack M, Luckow B, Nelson PJ, Cihak J, Simmons G,Clapham PR, et al. Aminooxypentane-RANTES in-duces CCR5 internalization but inhibits recycling: anovel inhibitory mechanism of HIV infectivity. J ExpMed. 1998;187:1215-24.

29. Luster AD. The role of chemokines in linking innateand adaptive immunity. Curr Opin Immunol. 2002;14:129-35.

30. Forster R, Mattis AE, Kremmer E, Wolf E, Brem G,Lipp M. A putative chemokine receptor, BLR1, di-rects B cell migration to defined lymphoid organsand specific anatomic compartments of the spleen.Cell. 1996;87:1037-47.

31. Serbina NV, Pamer EG. Monocyte emigration frombone marrow during bacterial infection requires sig-nals mediated by chemokine receptor CCR2. NatImmunol. 2006;7:311-7.

32. Yoshimura T, Matsushima K, Tanaka S, Robinson EA,Appella E, Oppenheim JJ, et al. Purification of ahuman monocyte-derived neutrophil chemotacticfactor that has peptide sequence similarity to otherhost defense cytokines. Proc Natl Acad Sci U S A.1987;84:9233-7.

33. Walz A, Peveri P, Aschauer H, Baggiolini M. Purifi-cation and amino acid sequencing of NAF, a novelneutrophil-activating factor produced by mono-cytes. Biochem Biophys Res Commun. 1987;149:755-61.

34. Matsushima K, Oppenheim JJ. Interleukin 8 andMCAF: novel inflammatory cytokines inducible by IL1 and TNF. Cytokine. 1989;1:2-13.

35. Baggiolini M, Walz A, Kunkel SL. Neutrophil-activat-ing peptide-1/interleukin 8, a novel cytokine that
activates neutrophils. J Clin Invest. 1989;84:1045-9.
36. Gerritsma JS, van Kooten C, Gerritsen AF, van Es LA,Daha MR. Transforming growth factor-beta 1 regu-lates chemokine and complement production byhuman proximal tubular epithelial cells. Kidney Int.1998;53:609-16.

37. Tang S, Leung JC, Abe K, Chan KW, Chan LY, ChanTM, et al. Albumin stimulates interleukin-8 expres-sion in proximal tubular epithelial cells in vitro andin vivo. J Clin Invest. 2003;111:515-27.

38. Wada T, Tomosugi N, Naito T, Yokoyama H, Koba-yashi K, Harada A, et al. Prevention of proteinuria bythe administration of anti-interleukin 8 antibody inexperimental acute immune complex-induced glo-merulonephritis. J Exp Med. 1994;180:1135-40.

39. Wada T, Yokoyama H, Tomosugi N, Hisada Y, OhtaS, Naito T, et al. Detection of urinary interleukin-8 inglomerular diseases. Kidney Int. 1994;46:455-60.

40. Segerer S, Henger A, Schmid H, Kretzler M, Dra-ganovici D, Brandt U, et al. Expression of the che-mokine receptor CXCR1 in human glomerular dis-eases. Kidney Int. 2006;69:1765-73.

41. Maus UA, Waelsch K, Kuziel WA, Delbeck T, MackM, Blackwell TS, et al. Monocytes are potent facili-tators of alveolar neutrophil emigration during lunginflammation: role of the CCL2-CCR2 axis. J Immu-nol. 2003;170:3273-8.

42. Araki M, Fahmy N, Zhou L, Kumon H, KrishnamurthiV, Goldfarb D, et al. Expression of IL-8 during reper-fusion of renal allografts is dependent on ischemictime. Transplantation. 2006;81:783-8.

43. van Gisbergen KP, Geijtenbeek TB, van Kooyk Y.Close encounters of neutrophils and DCs. TrendsImmunol. 2005;26:626-31.

44. Kurts C. Dendritic cells: not just another cell type inthe kidney, but a complex immune sentinel net-work. Kidney Int. 2006;70:412-4.

45. Kluth DC, Erwig LP, Rees AJ. Multiple facets ofmacrophages in renal injury. Kidney Int. 2004;66:542-57.

46. Sean Eardley K, Cockwell P. Macrophages and pro-gressive tubulointerstitial disease. Kidney Int. 2005;68:437-55.

47. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P,Littman DR, et al. A clonogenic bone marrow pro-genitor specific for macrophages and dendritic cells.Science. 2006;311:83-7.

48. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A,Locati M. The chemokine system in diverse forms ofmacrophage activation and polarization. Trends Im-munol. 2004;25:677-86.

49. Martinez FO, Gordon S, Locati M, Mantovani A. Tran-scriptional profiling of the human monocyte-to-mac-rophage differentiation and polarization: new mole-cules and patterns of gene expression. J Immunol.2006;177:7303-11.

50. Geissmann F, Jung S, Littman DR. Blood monocytesconsist of two principal subsets with distinct migra-tory properties. Immunity. 2003;19:71-82.

51. Weber C, Weber KS, Klier C, Gu S, Wank R, Horuk


R, et al. Specialized roles of the chemokinereceptors CCR1 and CCR5 in the recruitment ofmonocytes and T(H)1-like/CD45RO(�) T cells.Blood. 2001;97:1144-6.

52. Chen S, Bacon KB, Li L, Garcia GE, Xia Y, Lo D, et al.In vivo inhibition of CC and CX3C chemokine-in-duced leukocyte infiltration and attenuation of glo-merulonephritis in Wistar-Kyoto (WKY) rats byvMIP-II. J Exp Med. 1998;188:193-8.

53. Feng L, Chen S, Garcia GE, Xia Y, Siani MA, Botti P,et al. Prevention of crescentic glomerulonephritis byimmunoneutralization of the fractalkine receptorCX3CR1. Kidney Int. 1999;56:612-20.

54. Lloyd CM, Dorf ME, Proudfoot A, Salant DJ, Gutier-rez-Ramos JC. Role of MCP-1 and RANTES in inflam-mation and progression to fibrosis during murinecrescentic nephritis. J Leukoc Biol. 1997;62:676-80.

55. Anders HJ, Vielhauer V, Frink M, Linde Y, CohenCD, Blattner SM, et al. A chemokine receptor CCR-1antagonist reduces renal fibrosis after unilateral ure-ter ligation. J Clin Invest. 2002;109:251-9.

56. Eis V, Luckow B, Vielhauer V, Siveke JT, Linde Y,Segerer S, et al. Chemokine receptor CCR1 but notCCR5 mediates leukocyte recruitment and subse-quent renal fibrosis after unilateral ureteral obstruc-tion. J Am Soc Nephrol. 2004;15:337-47.

57. Tesch GH, Maifert S, Schwarting A, Rollins BJ, KelleyVR. Monocyte chemoattractant protein 1-dependentleukocytic infiltrates are responsible for autoim-mune disease in MRL-Fas(lpr) mice. J Exp Med.1999;190:1813-24.

58. Perez de Lema G, Maier H, Nieto E, Vielhauer V,Luckow B, Mampaso F, et al. Chemokine expressionprecedes inflammatory cell infiltration and chemo-kine receptor and cytokine expression during theinitiation of murine lupus nephritis. J Am Soc Neph-rol. 2001;12:1369-82.

59. de Lema GP, Maier H, Franz TJ, Escribese M, Chilla S,Segerer S, et al. Chemokine receptor Ccr2 defi-ciency reduces renal disease and prolongs survivalin MRL/lpr lupus-prone mice. J Am Soc Nephrol.2005;16:3592-601.

60. Bird JE, Giancarli MR, Kurihara T, Kowala MC, Val-entine MT, Gitlitz PH, et al. Increased severity ofglomerulonephritis in C-C chemokine receptor 2knockout mice. Kidney Int. 2000;57:129-36.

61. Anders HJ, Frink M, Linde Y, Banas B, Wornle M,Cohen CD, et al. CC Chemokine ligand 5/RANTESchemokine antagonists aggravate glomerulonephri-tis despite reduction of glomerular leukocyte infil-tration. J Immunol. 2003;170:5658-66.

62. Banchereau J, Steinman RM. Dendritic cells and thecontrol of immunity. Nature. 1998;392:245-52.

63. Wan H, Dupasquier M. Dendritic cells in vivo and invitro. Cell Mol Immunol. 2005;2:28-35.

64. Hume DA, Gordon S. Mononuclear phagocyte sys-tem of the mouse defined by immunohistochemicallocalization of antigen F4/80. J Exp Med. 1983;157:
1704-9.
65. van Kooyk Y, Geijtenbeek TB. DC-SIGN: escapemechanism for pathogens. Nat Rev Immunol. 2003;3:697-709.

66. Del Prete A, Locati M, Otero K, Riboldi E, MantovaniA, Vecchi A, et al. Migration of dendritic cells acrossblood and lymphatic endothelial barriers. ThrombHaemost. 2006;95:22-8.

67. Kruger T, Benke D, Eitner F, Lang A, Wirtz M, Ham-ilton-Williams EE, et al. Identification and functionalcharacterization of dendritic cells in the healthy mu-rine kidney and in experimental glomerulonephritis.J Am Soc Nephrol. 2004;15:613-21.

68. Niess JH, Brand S, Gu X, Landsman L, Jung S, Mc-Cormick BA, et al. CX3CR1-mediated dendritic cellaccess to the intestinal lumen and bacterial clear-ance. Science. 2005;307:254-8.

69. Dichmann S, Herouy Y, Purlis D, Rheinen H, Ge-bicke-Harter P, Norgauer J. Fractalkine induces che-motaxis and actin polymerization in human den-dritic cells. Inflamm Res. 2001;50:529-33.

70. Soos TJ, Sims TN, Barisoni L, Lin K, Littman DR,Dustin ML, et al. CX3CR1� interstitial dendritic cellsform a contiguous network throughout the entirekidney. Kidney Int. 2006;70:591-6.

71. Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojar-ski K, Watschinger B, Soleiman A, et al. Lymphaticneoangiogenesis in human kidney transplants is as-sociated with immunologically active lymphocyticinfiltrates. J Am Soc Nephrol. 2004;15:603-12.

72. Sanchez-Sanchez N, Riol-Blanco L, Rodriguez-Fer-nandez JL. The multiple personalities of the chemo-kine receptor CCR7 in dendritic cells. J Immunol.2006;176:5153-9.

73. Dong X, Swaminathan S, Bachman L, Croatt A, NathC, Griffin M. Resident dendritic cells are the predom-inant TNF-secreting cell in early renal ischemia/reperfusion injury. Kidney Int. 2007. In press.

74. Angeli V, Ginhoux F, Llodra J, Quemeneur L,Frenette PS, Skobe M, et al. B cell-driven lym-phangiogenesis in inflamed lymph nodes enhancesdendritic cell mobilization. Immunity. 2006;24:203-15.

75. Martin F, Chan AC. B cell immunobiology in disease:evolving concepts from the clinic. Annu Rev Immu-nol. 2006;24:467-96.

76. Edwards JC, Cambridge G. B-cell targeting in rheu-matoid arthritis and other autoimmune diseases. NatRev Immunol. 2006;6:394-403.

77. Novobrantseva TI, Majeau GR, Amatucci A, Kogan S,Brenner I, Casola S, et al. Attenuated liver fibrosisin the absence of B cells. J Clin Invest. 2005;115:3072-82.

78. Silverman GJ. Therapeutic B cell depletion and regen-eration in rheumatoid arthritis: emerging patterns andparadigms. Arthritis Rheum. 2006;54:2356-67.

79. Hardtke S, Ohl L, Forster R. Balanced expression ofCXCR5 and CCR7 on follicular T helper cells deter-
mines their transient positioning to lymph node fol-

1

1

1

1

1

1

1

1

1


licles and is essential for efficient B-cell help. Blood.2005;106:1924-31.

80. Cyster JG, Ngo VN, Ekland EH, Gunn MD, SedgwickJD, Ansel KM. Chemokines and B-cell homing tofollicles. Curr Top Microbiol Immunol. 1999;246:87-93.

81. Okada T, Cyster JG. B cell migration and interactionsin the early phase of antibody responses. Curr OpinImmunol. 2006;18:278-85.

82. Reif K, Ekland EH, Ohl L, Nakano H, Lipp M, ForsterR, et al. Balanced responsiveness to chemoattrac-tants from adjacent zones determines B-cell posi-tion. Nature. 2002;416:94-9.

83. Muller G, Lipp M. Concerted action of the chemo-kine and lymphotoxin system in secondary lym-phoid-organ development. Curr Opin Immunol.2003;15:217-24.

84. Kanemitsu N, Ebisuno Y, Tanaka T, Otani K, Ha-yasaka H, Kaisho T, et al. CXCL13 is an arrest che-mokine for B cells in high endothelial venules.Blood. 2005;106:2613-8.

85. Ebisuno Y, Tanaka T, Kanemitsu N, Kanda H,Yamaguchi K, Kaisho T, et al. Cutting edge: the Bcell chemokine CXC chemokine ligand 13/B lym-phocyte chemoattractant is expressed in the highendothelial venules of lymph nodes and Peyer’spatches and affects B cell trafficking across highendothelial venules. J Immunol. 2003;171:1642-6.

86. Sarwal M, Chua MS, Kambham N, Hsieh SC, Satter-white T, Masek M, et al. Molecular heterogeneity inacute renal allograft rejection identified by DNA mi-croarray profiling. N Engl J Med. 2003;349:125-38.

87. Steinmetz OM, Panzer U, Kneissler U, Harendza S,Lipp M, Helmchen U, et al. BCA-1/CXCL13 expres-sion is associated with CXCR5-positive B-cell clusterformation in acute renal transplant rejection. KidneyInt. 2005;67:1616-21.

88. Heller F, Cohen CD, Lindenmeyer MT, Brandt U,Draganovici D, Fischereder M, et al. The contribu-tion of B cells to renal interstitial inflammation. Am JPathol. 2007;170:457-68.

89. Takahama Y. Journey through the thymus: stromalguides for T-cell development and selection. Nat RevImmunol. 2006;6:127-35.

90. Romagnani S. Regulation of the T cell response. ClinExp Allergy. 2006;36:1357-66.

91. Harrington LE, Mangan PR, Weaver CT. Expandingthe effector CD4 T-cell repertoire: the Th17 lineage.Curr Opin Immunol. 2006;18:349-56.

92. Weaver CT, Harrington LE, Mangan PR, Gavrieli M,Murphy KM. Th17: an effector CD4 T cell lineagewith regulatory T cell ties. Immunity. 2006;24:677-88.

93. Ziegler SF. FOXP3: of mice and men. Annu RevImmunol. 2006;24:209-26.

94. Colantonio L, Iellem A, Sinigaglia F, D’Ambrosio D.Skin-homing CLA� T cells and regulatory CD25� T
cells represent major subsets of human peripheral
blood memory T cells migrating in response toCCL1/I-309. Eur J Immunol. 2002;32:3506-14.

95. Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, et al. Unique chemotacticresponse profile and specific expression of chemo-kine receptors CCR4 and CCR8 by CD4(�)CD25(�)regulatory T cells. J Exp Med. 2001;194:847-53.

96. Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P, et al. Bone marrow is a reser-voir for CD4�CD25� regulatory T cells that trafficthrough CXCL12/CXCR4 signals. Cancer Res. 2004;64:8451-5.

97. Lim HW, Broxmeyer HE, Kim CH. Regulation oftrafficking receptor expression in human forkheadbox P3� regulatory T cells. J Immunol. 2006;177:840-51.

98. Bystry RS, Aluvihare V, Welch KA, Kallikourdis M,Betz AG. B cells and professional APCs recruitregulatory T cells via CCL4. Nat Immunol. 2001;2:1126-32.

99. Lee I, Wang L, Wells AD, Dorf ME, Ozkaynak E,Hancock WW. Recruitment of Foxp3� T regulatorycells mediating allograft tolerance depends on theCCR4 chemokine receptor. J Exp Med. 2005;201:1037-44.

00. Schaniel C, Pardali E, Sallusto F, Speletas M, Ruedl C,Shimizu T, et al. Activated murine B lymphocytesand dendritic cells produce a novel CC chemokinewhich acts selectively on activated T cells. J ExpMed. 1998;188:451-63.

01. Mahajan D, Wang Y, Qin X, Wang Y, Zheng G, WangYM, et al. CD4�CD25� regulatory T cells protectagainst injury in an innate murine model of chronickidney disease. J Am Soc Nephrol. 2006;17:2731-41.

02. Wang YM, Zhang GY, Wang Y, Hu M, Wu H, WatsonD, et al. Foxp3-transduced polyclonal regulatory Tcells protect against chronic renal injury from adria-mycin. J Am Soc Nephrol. 2006;17:697-706.

03. Muthukumar T, Dadhania D, Ding R, Snopkowski C,Naqvi R, Lee JB, et al. Messenger RNA for FOXP3 inthe urine of renal-allograft recipients. N Engl J Med.2005;353:2342-51.

04. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A.Circulating fibrocytes define a new leukocyte sub-population that mediates tissue repair. Mol Med.1994;1:71-81.

05. Quan TE, Cowper SE, Bucala R. The role of circulat-ing fibrocytes in fibrosis. Curr Rheumatol Rep. 2006;8:145-50.

06. Opalenik SR, Davidson JM. Fibroblast differentiationof bone marrow-derived cells during wound repair.FASEB J. 2005;19:1561-3.

07. Moore BB, Kolodsick JE, Thannickal VJ, Cooke K,Moore TA, Hogaboam C, et al. CCR2-mediated re-cruitment of fibrocytes to the alveolar space afterfibrotic injury. Am J Pathol. 2005;166:675-84.

08. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray
LA, Xue YY, et al. Circulating fibrocytes traffic to the

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1


lungs in response to CXCL12 and mediate fibrosis.J Clin Invest. 2004;114:438-46.

09. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN.Peripheral blood fibrocytes: differentiation pathwayand migration to wound sites. J Immunol. 2001;166:7556-62.

10. Sakai N, Wada T, Yokoyama H, Lipp M, Ueha S,Matsushima K, et al. Secondary lymphoid tissue che-mokine (SLC/CCL21)/CCR7 signaling regulates fi-brocytes in renal fibrosis. Proc Natl Acad Sci U S A.2006;103:14098-103.

11. Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM, et al.Loss of the tumor suppressor Vhlh leads to upregu-lation of Cxcr4 and rapidly progressive glomerulo-nephritis in mice. Nat Med. 2006;12:1081-7.

12. Togel F, Isaac J, Hu Z, Weiss K, Westenfelder C.Renal SDF-1 signals mobilization and homing ofCXCR4-positive cells to the kidney after ischemicinjury. Kidney Int. 2005;67:1772-84.

13. Segerer S, Banas B, Wornle M, Schmid H, Cohen CD,Kretzler M, et al. CXCR3 is involved in tubulointer-stitial injury in human glomerulonephritis. Am JPathol. 2004;164:635-49.

14. Segerer S, Mac KM, Regele H, Kerjaschki D, Schlon-dorff D. Expression of the C-C chemokine receptor5 in human kidney diseases. Kidney Int. 1999;56:52-64.

15. Segerer S, Cui Y, Hudkins KL, Goodpaster T, EitnerF, Mack M, et al. Expression of the chemokinemonocyte chemoattractant protein-1 and its recep-tor chemokine receptor 2 in human crescenticglomerulonephritis. J Am Soc Nephrol. 2000;11:2231-42.

16. Masaki T, Chow F, Nikolic-Paterson DJ, Atkins RC,Tesch GH. Heterogeneity of antigen expression ex-plains controversy over glomerular macrophage ac-cumulation in mouse glomerulonephritis. NephrolDial Transplant. 2003;18:178-81.

17. Steinmetz O, Sadaghiani S, Panzer U, Krebs C,Meyer-Schwesinger C, Streichert T, et al. Antihyper-tensive therapy induces compartment specific che-
mokine expression and a Th1 immune response in
the clipped kidney of Goldblatt hypertensive rats.Am J Physiol Renal Physiol. 2007;292:F876-87.

18. Panzer U, Steinmetz OM, Reinking RR, Meyer TN,Fehr S, Schneider A, et al. Compartment-specificexpression and function of the chemokine IP-10/CXCL10 in a model of renal endothelial microvascu-lar injury. J Am Soc Nephrol. 2006;17:454-64.

19. Proudfoot AE, Handel TM, Johnson Z, Lau EK, Li-Wang P, Clark-Lewis I, et al. Glycosaminoglycanbinding and oligomerization are essential for the invivo activity of certain chemokines. Proc Natl AcadSci U S A. 2003;100:1885-90.

20. Tanaka Y, Adams DH, Hubscher S, Hirano H, Sieben-list U, Shaw S. T-cell adhesion induced by proteo-glycan-immobilized cytokine MIP-1 beta. Nature.1993;361:79-82.

21. Segerer S, Djafarzadeh R, Gröne HJ, Weingart C,Kerjaschki D, Weber C, et al. Selective binding andpresentation of CCL5 by discrete tissue microenvi-ronments during renal inflammation. J Am SocNephrol. In press, 2007.

22. Horuk R, Wang ZX, Peiper SC, Hesselgesser J. Iden-tification and characterization of a promiscuous che-mokine-binding protein in a human erythroleukemiccell line. J Biol Chem. 1994;269:17730-3.

23. Segerer S, Bohmig GA, Exner M, Colin Y, Cartron JP,Kerjaschki D, et al. When renal allografts turn darc.Transplantation. 2003;75:1030-4.

24. Segerer S, Regele H, Mack M, Kain R, Cartron JP,Colin Y, et al. The duffy antigen receptor for che-mokines is up-regulated during acute renal trans-plant rejection and crescentic glomerulonephritis.Kidney Int. 2000;58:1546-56.

25. Amano H, Bickerstaff A, Orosz CG, Novick AC,Toma H, Fairchild RL. Absence of recipient CCR5promotes early and increased allospecific antibodyresponses to cardiac allografts. J Immunol. 2005;174:6499-508.

26. Pfoertner S, Jeron A, Probst-Kepper M, Guzman CA,Hansen W, Westendorf AM, et al. Signatures of hu-man regulatory T cells: an encounter with old
friends and new players. Genome Biol. 2006;7:R54.

Role of Chemokines for the Localization of Leukocyte Subsets in the

Documents

Transcript of Role of Chemokines for the Localization of Leukocyte Subsets in the