title: NOD2: a potential target for regulating liver injury.
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.
authors.affiliation: INSERM U795, Lille, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Body-Malapel
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dharancy
authors.forename: Dominique
authors.initials: D
authors.lastname: Berrebi
authors.forename: Alexandre
authors.initials: A
authors.lastname: Louvet
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hugot
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chareyre
authors.forename: Gilles
authors.initials: G
authors.lastname: Pages
authors.forename: Emilie
authors.initials: E
authors.lastname: Gantier
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Irène
authors.initials: I
authors.lastname: Garcia
authors.forename: Sylvie
authors.initials: S
authors.lastname: Hudault
authors.forename: Filoména
authors.initials: F
authors.lastname: Conti
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.forename: Laurent
authors.initials: L
authors.lastname: Dubuquoy
authors.forename: Philippe
authors.initials: P
authors.lastname: Mathurin
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D003208:Concanavalin A / Q000633:toxicity; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000032:analysis / Q000494:pharmacology; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008099:Liver / Q000293:injuries*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000032:analysis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000276:Adjuvants, Immunologic; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007371:Interferon-gamma