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NOD2: a potential target for regulating liver injury

Body-Malapel, Mathilde
Dharancy, Sebastien
Berrebi, Dominique
Louvet, Alexandre
Hugot, J. P.
Philpott, D. J.
Giovannini, Marco
Chareyre, Fabrice
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Published in Laboratory Investigation. 2008, vol. 88, no. 3, p. 318-327
Abstract The recent discovery of bacterial receptors such as NOD2 that contribute to crosstalk between innate and adaptive immune systems in the digestive tract constitutes an important challenge in our understanding of liver injury mechanisms. The present study focuses on NOD2 functions during liver injury. NOD2, TNF-alpha and IFN-gamma mRNA were quantified using real-time PCR in liver samples from patients and mice with liver injury. We evaluated the susceptibility of concanavalin A (ConA) challenge in NOD2-deficient mice (Nod2-/-) compared to wild-type littermates. We tested the effect of muramyl dipeptide (MDP), the specific activator of NOD2, on ConA-induced liver injury in C57BL/6 mice. We studied the cellular distribution and the role of NOD2 in immune cells and hepatocytes. We demonstrated that NOD2, TNF-alpha and IFN-gamma were upregulated during liver injury in mice and humans. Nod2-/- mice were resistant to ConA-induced hepatitis compared to their wild-type littermates, through reduced IFN-gamma production by immune cells. Conversely, administration of MDP exacerbated ConA-induced liver injury. MDP was a strong inducer of IFN-gamma in freshly isolated human PBMC, splenocytes and hepatocytes. Our study supports the hypothesis that NOD2 contributes to liver injury via a regulatory mechanism affecting immune cells infiltrating the liver and hepatocytes. Taken together, our results indicate that NOD2 may represent a new therapeutic target in liver diseases.
Keywords Acetylmuramyl-Alanyl-Isoglutamine/pharmacologyAdjuvants, Immunologic/pharmacologyAnimalsApoptosisCase-Control StudiesCell Separation/methodsCells, CulturedConcanavalin A/toxicityHepatitis, Animal/chemically induced/*immunology/metabolism/pathologyHepatocytes/drug effects/metabolism/physiologyHumansImmunity, InnateInterferon-gamma/analysis/pharmacologyKineticsLeukocytes, Mononuclear/drug effects/*immunologyLiver/*injuriesMiceMice, Inbred C57BLMice, KnockoutNod2 Signaling Adaptor Protein/analysis/*deficiency/genetics/*metabolismRNA, Messenger/metabolismSpleen/cytology/drug effectsTumor Necrosis Factor-alpha/analysis/pharmacologyUp-Regulation
Stable URL http://archive-ouverte.unige.ch/unige:11162
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PMID: 18227809
Research group Rôles des cytokines de la famille du TNF dans les infections mycobactériennes (500)
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