RIPK1 in Liver Parenchymal Cells Limits Murine Hepatitis during Acute CCl(4)-Induced Liver Injury

Some life-threatening acute hepatitis originates from drug-induced liver injury (DILI). Carbon tetrachloride (CCl(4))-induced acute liver injury in mice is the widely used model of choice to study acute DILI, which pathogenesis involves a complex interplay of oxidative stress, necrosis, and apoptosis. Since the receptor interacting protein kinase-1 (RIPK1) is able to direct cell fate towards survival or death, it may potentially affect the pathological process of xenobiotic-induced liver damage. Two different mouse lines, either deficient for Ripk1 specifically in liver parenchymal cells (Ripk1(LPC-KO)) or for the kinase activity of RIPK1 (Ripk1(K45A), kinase dead), plus their respective wild-type littermates (Ripk1(fl/fl), Ripk1(wt/wt)), were exposed to single toxic doses of CCl(4). This exposure led in similar injury in Ripk1(K45A) mice and their littermate controls. However, Ripk1(LPC-KO) mice developed more severe symptoms with massive hepatocyte apoptosis as compared to their littermate controls. A pretreatment with a TNF-α receptor decoy exacerbated liver apoptosis in both Ripk1(fl/fl) and Ripk1(LPC-KO) mice. Besides, a FasL antagonist promoted hepatocyte apoptosis in Ripk1(fl/fl) mice but reduced it in Ripk1(LPC-KO) mice. Thus, the scaffolding properties of RIPK1 protect hepatocytes from apoptosis during CCl(4) intoxication. TNF-α and FasL emerged as factors promoting hepatocyte survival. These protective effects appeared to be independent of RIPK1, at least in part, for TNF-α, but dependent on RIPK1 for FasL. These new data complete the deciphering of the molecular mechanisms involved in DILI in the context of research on their prevention or cure.