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Rheumatol IntDOI 10.1007/s00296-014-2975-5

RevIew ARtIcle

Potential roles of nucleotide‑binding oligomerization domain 2 in the pathogenesis of systemic lupus erythematosus

Jing Li · Song Wu · Ming‑Rui Wang · Ting‑Ting Wang · Bai‑kun Li · Ji‑Min Zhu

Received: 11 December 2013 / Accepted: 17 February 2014 © Springer-verlag Berlin Heidelberg 2014

Introduction

Systemic lupus erythematosus (Sle) is a systemic autoim-mune disease, characterized by a diverse array of autoanti-body production, immune complexes deposition and com-plement activation, resulting in multiple system and organ involvement [1]. the etiology of Sle remains unclear; genetic susceptibility, environmental factors, sexual hor-mone disorder and immune dysfunction are thought to con-tribute to the disease development.

there is evidence that the pattern recognition receptors (PRRs) dysfunction is associated with numerous immune disorders, such as Sle [2]. PRRs can alert and activate the innate immune system through recognizing the con-served molecular patterns to distinguish pathogen-associ-ated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). However, excessive signaling may induce immune responses that are harmful to the host.

Being the most studied PRRs, toll-like receptors (tlRs)-mediated intracellular signaling is a crucial link between innate and adaptive immunity, and the role of tlRs in the pathogenesis of Sle has been fully elucidated [3–5]. Besides tlRs, cytoplasmic nucleotide-binding oligom-erisation domain (NOD)-like receptors (NlRs) are a new family of PRRs for the recognition of extracellular PAMPs [6, 7]. NOD2 is one of well-characterized members of the NlRs family. In recent years, there are increasing evi-dences to show that NOD2 may contribute to the develop-ment of pathogenesis in numerous auto inflammatory and autoimmune disorders [8–10]. Mutations in NOD2 were particularly identified to be associated with an increased risk of crohn’s disease, Blau syndrome and asthma [11, 12]. However, researches focusing on the relationship between NOD2 and Sle are fewer. lately, a research team began to investigate the role of NOD2 in Sle [13,

Abstract Nucleotide-binding oligomerization domain 2 (NOD2) is one of the most prominent member of the NOD-like receptors protein family that functions as intracellu-lar pattern recognition receptors. Numerous studies have suggested the importance of NOD2 in defensing against microbial infections, regulation of the inflammatory pro-cess. It is shown that NOD2 contributes to the pathogen-esis of various autoimmune and chronic inflammatory dis-eases, such as crohn’s disease, rheumatoid arthritis. the aim of this study is to summarize our current understand-ings of NOD2 function and the role of NOD2 in systemic lupus erythematosus (Sle). the following databases were searched: Pubmed, eMBASe and web of Science for eng-lish-language sources, using the terms “lupus,” “systemic lupus erythematosus,” ‘‘Sle,” “immunity,” “inflammatory” and “NOD2.” emerging data evidences that NOD2 has important biological effects in autoimmunity and inflam-matory and might take part in the pathogenesis of Sle. Studies exploring the relationship between NOD2 and Sle are very limited. whether NOD2 could be a potentially val-uable therapeutic target for treatment for Sle, more under-standing of the mechanism of NOD2 is needed in the future in Sle.

Keywords NOD2 · Systemic lupus erythematosus · therapeutic target · Immune

J. li · S. wu · M.-R. wang · t.-t. wang · B. li · J.-M. Zhu (*) Department of Public Health and General Medicine, School of Integrated traditional and western Medicine, Anhui University of chinese Medicine, Hefei 230038, Anhui, chinae-mail: zhjmcdc@126.com

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14]. they have detected that the expression of NOD2 in monocytes increased in Sle patients compared to healthy controls. the reason remains not completely clear. In this review, we will briefly discuss the biological features of NOD2 and its potential role in Sle.

Search strategy

we used the keywords “lupus,” “systemic lupus erythema-tosus,” “Sle,” “immunity,” “inflammatory” and “NOD2” to search the following databases: Pubmed, eMBASe and web of Science. we included the studies published in the english language.

NOD2

NlRs are multidomain proteins that contain a c-terminal leucine-rich-repeat (lRR) domain, a central NOD domain and an N-terminal effector domain, and the NlRs fam-ily is consisted of 22 members in humans and 34 in mice [15, 16]. NlR proteins play an important role in detecting inflammatory stimuli and subsequently mediate inflamma-some assembly [17].

NOD2, also known as caspase recruitment domain-containing protein 15 (cARD15), was initially discovered by Nunez’s group in 2001 through homology to plant dis-ease-resistance (R) gene [18]. Up to now, it is one of the widely studied members of NlRs. the human NOD2 gene is located on chromosome 16q12. It has 12 exons and spans 36 kilobases. More than two hundred single nucleotide pol-ymorphisms have been identified in the NOD2 gene. the protein of NOD2 comprises 1,040 amino acids, containing 2 N-terminal cARDs, a centrally located NOD and multi-ple c-terminal lRRs [19]. NOD2 is mainly expressed in dendritic cells (Dcs) [20], macrophages [18], paneth cells [21] and intestinal, lung and oral epithelial cells [22–24].

Normal functions of the NOD2 gene/protein are defense against microbial infections, regulation of the inflammatory process and apoptosis [25, 26]. In the cytoplasm, NOD2 as a general sensor recognizes muropeptide structures derived from peptidoglycan (PGN), a major component of bacterial cell walls through its c-terminal lRRs. the minimal motif detected by NOD2 is muramyl dipeptide (MDP), which is found in the PGN of nearly all gram-positive and gram-neg-ative bacteria [27, 28]. However, the mechanism by which these agonists cross the host’s cell membrane to stimulate NOD2 remains not explained in detail. Upon ligand recog-nition, NOD2 undergoes a conformational change and the NOD domain oligomerizes and initiates the recruitment of receptor-interacting protein 2 (RIP2). Subsequently the cARDs of NOD2 bind the cARD domain of RIP2 through a homotypic cARD–cARD interaction, leading to the

activation of multiple signaling pathways and the produc-tion of pro-inflammatory cytokines. Several studies have identified that NOD2 agonists have a synergistic effect on tlRs-mediated inflammatory cytokines production, which could potentiate the cellular response against patho-gens [20, 29, 30]. Besides recognition bacteria, NOD2 was also shown to play a role in host antiviral defense mecha-nisms [31, 32]. After recognition of a viral ssRNA genome, NOD2 used the adaptor protein, called mitochondrial anti-viral signaling (MAvS) protein to activate interferon-regu-latory factor 3 (IRF3) and product interferon-beta (IFN-β). NOD2-deficient mice failed to produce IFN efficiently and increased the chance of diseases induced by virus. Based on the above data, it is concluded that NOD2 has a multi-faceted role in pathogen detection.

Recent researches have found that NOD2 not only takes part in the first line of defense against invading pathogens of innate immune response, but also contributes to the adaptive immune response [33, 34]. In one study, van Bee-len et al. found that upon sensing bacterial NOD2-ligand MDP, Dcs promoted the development of human th17 cells from memory th cell and the production of Il-17 via enhanced expression of Il-23 and Il-1. In another mice model study, it is shown that MDP stimulated NOD2 trig-gered a potent Ag-specific immune response with a th2-type polarization profile, and NOD2 was critical for the induction of both th1- and th2-type responses following costimulation with tlR agonists [35]. Furthermore, Shaw et al. demonstrated that NOD2−/− cD4+ t cells had the poor helper t cell differentiation, which was associated with impaired production of Il-2 [36].

there is evidence that NOD2 also plays a role in apop-tosis. It regulates the activation of procaspase 9, which con-tains a cARD in its structure, via the cARD–cARD inter-action, resulting in the induction of apoptosis [37].

NOD2 signaling

the mechanism of NOD2 signaling transduction and reg-ulation is complicated. to date, there have been several major signaling pathways identified in the NOD2 func-tioning. the NOD2-mediated NF-κB activation pathway has been extensively studied. In the process of signaling transduction, RIP2 acts as a key effector molecule down-stream of NOD2. Stimulation of NOD2 by its specific bacteria activators causes the recruitment of RIP2 through the cARD–cARD interaction. RIP2 can directly lead to ubiquitination of NF-κB essential modulator (NeMO) and thus the activation of the IKK complex (inhibitory IκB kinase). the IKK complex is also activated by tGF-β-activated kinase 1 (tAK1), which is downstream of tlR activation. Subsequently activated IKK relieves inhibition

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of NF-κB by phosphorylating IκB, resulting in releasing NF-κB for translocation to the nucleus and gene transcrip-tion [38, 39]. MDP recognition by NOD2 also leads to the activation of mitogen-activated protein kinases (MAPKs), including p38, c-Jun N-terminal kinase (JNK) and extracel-lular signal-regulated protein kinase (eRK) pathways [40]. Both NF-κB and MAPKs signaling pathways contribute to the NOD2-mediated inflammatory and immune response, including the secretion of pro-inflammatory cytokines such as interleukin-6 (Il-6), tumor necrosis factor alpha (tNF-α) and Il-1β [28].

Besides participating in the NF-κB and MAPKs signal-ing, NOD2 can also function as a viral PRR and participate in inducing antiviral signaling. the pathway involves ssRNA virus-induced activation of NOD2, which binds to MAvS, leading to IRF3 activation and interferon gene expression [41].

Autophagy has emerged as a critical pathway of host defense against bacterial infection. It is a highly conserved self-degradation system that plays an important role in maintaining cellular homeostasis through the elimination of misfolded proteins and damaged organelles [42]. MDP induces autophagy in non-myeloid cells, such as fibro-blasts and epithelial cells, or myeloid monocytic cells, such as macrophages and Dcs, in a NOD2-dependent manner [43–45]. NOD2 triggers the pathway that does not engage the adaptor RIP2 but instead induces the recruitment of autophagy-related 16-like 1 (AtG16l1) to the site of bac-terial entry, where it triggers bacterial autophagy.

Potential roles of NOD2 in SLE

Due to the biological features, correa et al. [10] put for-ward that for inflammatory and autoimmune diseases where the severity of NOD2-mediated inflammation war-rants, it seems plausible that cycles of brief therapy with NOD2 inhibitor could potentially quiet inflammation, pro-duce remissions, and thus provide an opportunity for re-establishing immune homoeostasis.

Sle is a complex, systemic autoimmune disease char-acterized by multisystemic involvement presenting with numerous clinical manifestations. However, the etiology and pathogenesis mechanisms of Sle have not been clearly elucidated. Several researches have reported that th1, th2 and th17 contribute to the pathogenesis of chronic inflam-matory and autoimmune diseases including Sle [46]. Par-ticularly, deregulating production of Il-17 exerts a key effect in the pathogenesis of Sle. there are accumulating evidences to suggest that NOD2 may have an association with the regulation of Il-17. First, van Beelen et al. [33] found that bacteria, primed human Dcs to promote Il-17 production in memory th cells through the NOD2-ligand MDP. In NOD2-deficient crohn’s disease patients, Dcs had

an impaired capacity to induce Il-17 expression upon MDP triggering. In vieira et al. study [47], investigators detected that joint NOD2/RIP2 signaling regulated Il-17 axis and contributed to the development of experimental arthritis. the NOD2−/− mice was protected from Ag-induced arthri-tis (AIA). Furthermore, NOD2/RIP2 signaling contributed to triggering the Il-17-dependent joint immune response by managing the local production of proinflammatory cytokine (Il-6, Il-23 and Il-1β). In another study [48], the result indicated the NOD2 polymorphism influenced th2- and th17 cell responses in blood mononuclear cell from mul-tiple sclerosis (MS) patients. therefore, we consider NOD2 may take part in Sle by regulation of Il-17 (Fig. 1).

Besides th17, autophagy is also probably involved in the pathogenesis of Sle. Genome-wide association studies have pointed out that polymorphisms in the region of the autophagy gene autophagy protein 5 (AtG5) are associated with Sle [49, 50]. Moreover, drugs modulating autophagy such as rapamycin and the peptide P140 provide benefi-cial effects on the development of lupus [51–53]. Recently, more studies have explored the mechanism of autophagy in Sle. Alessandri et al. [54] detected that there were signifi-cant differences in spontaneous autophagy between cD4+ naive t cells from patients with Sle and healthy donors. Gros et al. [55] observed that t cells from two distinct lupus-prone mouse models exhibit high loads of autophagic compartments compared with controls. As B cells repre-sent a major player in Sle, clarke et al. found activation of autophagy in early developmental and transitional stages of B cell development in a lupus mouse model. Given the known roles of NOD2 in recruiting AtG16l1 to the bac-terial entry site, autophagy induction, we hypothesize that NOD2 may play an important role in the pathogenesis of lupus through autophagy (Fig. 1).

the NOD2 gene lies on 16q12 and several studies have shown that 16q12 is one of the susceptibility loci in Sle patient [56, 57]. Several studies explored the role of the NOD2 gene in Sle susceptibility in european-descent and Asian-descent population. Ferreiros-vidal et al. [58] detected that genotypes for the three NOD2 mutations (3020insc, 2722G>c and 2104c>t) had no significant dif-ferences between Sle patients and controls from the gen-eral population, as well as another three polymorphisms (rs2076756, rs2066843 and rs2066845) in NOD2 [59]. In addition, similar results were found in Hong Kong chi-nese population [60]. In contrast to the discussed above, a pooled analysis of existing published and unpublished data indicated that the allele of rs2066845 appears to have a strong effect on risk to Sle (OR 2.01; 95 % cI 1.01–4.03) [61]. Since the results were only according to specific pop-ulations, whether NOD2 polymorphisms truly predispose to Sle need be further explored with larger numbers of participants in multiple different ethnic populations.

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Apart from the association study between genetic muta-tions of NOD2 and Sle, Yu et al. [13] investigated the role of NOD2 in the peripheral antigen presenting cells (APcs), t, B lymphocytes, as well as the role of NOD2 in the modulation of pro-inflammatory cytokines induced by NOD2 ligand MDP of Sle patients and control subjects. the results showed that NOD2 expression in monocytes and pDcs were significantly increased in Sle patients with inactive disease who were not receiving immuno-suppressive treatment when compared to healthy controls. However, after immunosuppressant therapy, the expression of NOD2 in cD8+ t cells, monocytes, mDcs and pDcs in Sle decreased which subsequently reduced regulatory cytokine Il-10, allowing for an aberrant inflammatory response contributing toward the regulation of immuno-pathological mechanisms of Sle. the aggregate evidence indicated that NOD2 might play an important role in the pathogenesis of Sle and the discovery of NOD2 might initiate a new field of investigation for the development of new therapeutics in the treatment for Sle.

Conclusion

Based on the recent data, we conclude that NOD2 has a more multifaceted role during an immune response than first imagined. It may contribute to the pathogenesis of

many autoimmune diseases, such as cD, RA due to its bio-logical features and possibly provide a new approach for treatment. However, the studies exploring the relationship between NOD2 and Sle are very limited. In order to deter-mine whether NOD2 may indeed be a potentially valuable therapeutic target for treatment for Sle, further investiga-tions are needed to clarify the roles of NOD2 in the devel-opment and treatment for Sle in human.

Acknowledgments this work was supported by grants from the National Natural Science Foundation of china (30901255).

Conflict of interest the authors declare that they have no conflict of interest.

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