NOD2: a potential target for regulating liver injury.
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.
Body-Malapel
Mathilde
M
INSERM U795, Lille, France.
Dharancy
Sébastien
S
Berrebi
Dominique
D
Louvet
Alexandre
A
Hugot
Jean-Pierre
JP
Philpott
Dana J
DJ
Giovannini
Marco
M
Chareyre
Fabrice
F
Pages
Gilles
G
Gantier
Emilie
E
Girardin
Stephen E
SE
Garcia
Irène
I
Hudault
Sylvie
S
Conti
Filoména
F
Sansonetti
Philippe J
PJ
Chamaillard
Mathias
M
Desreumaux
Pierre
P
Dubuquoy
Laurent
L
Mathurin
Philippe
P
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
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