NOD2: a potential target for regulating liver injury

Body-Malapel, Mathilde; Dharancy, Sébastien; Berrebi, Dominique; Louvet, Alexandre; Hugot, Jean‐Pierre; Philpott, Dana J.; Giovannini, Marco; Chareyre, Fabrice; Pagès, Gilles; Gantier, Emilie; Girardin, Stephen E.; García, Irene; Hudault, Sylvie; Conti, Filoména; Sansonetti, Philippe J.; Chamaillard, Mathias; Desreumaux, Pierre; Dubuquoy, Laurent; Mathurin, Philippe

doi:10.1038/labinvest.3700716

Cited by 41 publications

(31 citation statements)

References 28 publications

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“…This is reminiscent of the reported increase in mortality induced by secondary bacterial infection in virally infected mice, which is mediated by NOD1 and NOD2 (26), and of the critical role of NOD2 in severe liver injury (72). In the context of HCV infection, NS5B, in parallel to directly inducing inflammatory cytokines, might sensitize patients to bacterial in- …”

Section: Discussionmentioning

confidence: 91%

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase

Vegna

Grégoire

Moreau

et al. 2016

J Virol

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Hepatitis C virus (HCV) triggers innate immunity signaling in the infected cell. Replication of the viral genome is dispensable for this phenotype, and we along with others have recently shown that NS5B, the viral RNA-dependent RNA polymerase, synthesizes double-stranded RNA (dsRNA) from cellular templates, thus eliciting an inflammatory response, notably via activation of type I interferon and lymphotoxin ␤. Here, we investigated intracellular signal transduction pathways involved in this process. Using HepaRG cells, a model that largely recapitulates the in vivo complexities of the innate immunity receptor signaling, we have confirmed that NS5B triggered increased expression of the canonical pattern recognition receptors (PRRs) specific for dsRNA, namely, RIG-I, MDA5, and Toll-like receptor 3 (TLR3). Unexpectedly, intracellular dsRNA also led to accumulation of NOD1, a receptor classically involved in recognition of bacterial peptidoglycans. NOD1 activation, confirmed by analysis of its downstream targets, was likely due to its interaction with dsRNA and was independent of RIG-I and mitochondrial antiviral signaling protein (MAVS/IPS-1/Cardif/VISA) signaling. It is likely to have a functional significance in the cellular response in the context of HCV infection since interference with the NOD1 pathway severely reduced the inflammatory response elicited by NS5B. IMPORTANCEIn this study, we show that NOD1, a PRR that normally senses bacterial peptidoglycans, is activated by HCV viral polymerase, probably through an interaction with dsRNA, suggesting that NOD1 acts as an RNA ligand recognition receptor. In consequence, interference with NOD1-mediated signaling significantly weakens the inflammatory response to dsRNA. These results add a new level of complexity to the understanding of the cross talk between different classes of pattern recognition receptors and may be related to certain complications of chronic hepatitis C virus infection.

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Section: Discussionmentioning

confidence: 91%

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase

Vegna

Grégoire

Moreau

et al. 2016

J Virol

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“…25 The NOD2 upregulation in atheroma lesions indicates an involvement of this protein in the pathology of CHD. 26 Our data showed that cardiac NOD2 increased after AB surgery in the cardiomyocyte cytoplasm, which suggests that the upregulated NOD2 is involved in AB-induced hypertrophy (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…11,24 NOD2 may represent a new therapeutic target in liver diseases. 25 However, the biochemical mechanism by which NOD2 mediates its antihypertrophic effects remains elusive. The development of cardiac hypertrophy is complex.…”

Section: Discussionmentioning

confidence: 99%

NOD2 deletion promotes cardiac hypertrophy and fibrosis induced by pressure overload

Zong

Salim

Zhou

et al. 2013

Laboratory Investigation

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Nucleotide-binding oligomerization domain-2 (NOD2, also designated CARD15), a member of the NOD-leucine-rich repeat (LRR) protein family (also called the CATERPILLAR family), is upregulated in atheroma lesions and has an important role in regulating the intracellular recognition of bacterial components by immune cells. However, the effect of NOD2 on cardiac hypertrophy induced by a pathological stimulus has not been determined. Here, we investigated the effects of NOD2 deficiency on cardiac hypertrophy induced by aortic banding (AB) in mice. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. NOD2 expression was upregulated in cardiomyocytes after aortic banding surgery in wild-type (WT) mice. NOD2 deficiency promoted cardiac hypertrophy and fibrosis 4 weeks after AB. Further, the enhanced activation of TLR4 and the MAPKs, NF-kB and TGF-b/Smad pathways were found in NOD2-knockout (KO) mice compared with WT mice. Our results suggest that NOD2 attenuates cardiac hypertrophy and fibrosis via regulation of multiple pathways.

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“…Overexpression of NOD2 led to enhanced RNase-L activity in cells, suggesting that NOD2 may accelerate the degradation of transgene mRNA derived from HDAd via activation of RNase-L in transduced cells instead of by chromatin modification. NOD2 expression is also up-regulated by pro-inflammatory stimuli in liver cells (e.g., hepatocytes) (Body-Malapel et al, 2008), suggesting that transgene mRNA derived from HDAd in hepatocytes may also be degraded by RNase-L that is activated by interaction of OAS2 with NOD2 during an HDAd-dependent pro-inflammatory response. Our current and previous results suggest that HDAd-transduced cells may accelerate silencing of transgene expression at the transcriptional level by both dependent and independent epigenetic modification of vector DNA (Suzuki et al, 2010b).…”

Section: Nod2 Contributes Innate Response To Hdadsmentioning

confidence: 99%

“…NOD2 senses bacterial peptidoglycan released during phagocytosis and transported into the cell by endocytosis (Lecat et al, 2010). Although endogenous NOD2 expression is restricted in myelomonocytic cells (e.g., macrophages), NOD2 expression is also up-regulated by pro-inflammatory stimuli in liver cells (e.g., hepatocytes) of mice and humans (Body-Malapel et al, 2008). After systemic administration, over 80% of Ad5-based vectors distribute in livers of mice and nonhuman primates (Sakurai et al, 2008).…”

Section: Nod2 Contributes Innate Response To Hdadsmentioning

confidence: 99%

NOD2 Signaling Contributes to the Innate Immune Response Against Helper-Dependent Adenovirus Vectors Independently of MyD88 In Vivo

Suzuki

Cela²,

Bertin³

et al. 2011

Human Gene Therapy

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We previously demonstrated that Toll-like receptor/myeloid differentiation primary response gene 88 (MyD88) signaling is required for maximal innate and acquired [T helper cell type 1 (Th1)] immune responses following systemic administration of helper-dependent adenoviral vectors (HDAds). However, MyD88-deficient mice injected with HDAdLacZ exhibited only partial reduction of innate immune cytokine expression compared with wild-type mice, suggesting MyD88-independent pathways also respond to HDAds. We now show that NOD2, a nucleotide-binding and oligomerization domain (NOD)-like receptor known to detect muramyl dipeptides in bacterial peptidoglycans, also contributes to innate responses to HDAds, but not to humoral or Th1 immune responses. We established NOD2/MyD88 double-deficient mice that, when challenged with HDAds, showed a significant reduction of the innate response compared with mice deficient for either gene singly, suggesting that NOD2 signaling contributes to the innate response independently of MyD88 signaling following systemic administration of HDAds. In addition, NOD2-deficient mice exhibited significantly higher transgene expression than did wild-type mice at an early time point (before development of an acquired response), but not at a later time point (after development of an acquired response). These results indicate that the intracellular sensor NOD2 is required for innate responses to HDAds and can limit transgene expression during early phases of infection.

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NOD2: a potential target for regulating liver injury

Cited by 41 publications

References 28 publications

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase

NOD1 Participates in the Innate Immune Response Triggered by Hepatitis C Virus Polymerase

NOD2 deletion promotes cardiac hypertrophy and fibrosis induced by pressure overload

NOD2 Signaling Contributes to the Innate Immune Response Against Helper-Dependent Adenovirus Vectors Independently of MyD88 In Vivo

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