RIPK1 in Liver Parenchymal Cells Limits Murine Hepatitis during Acute CCl-Induced Liver Injury.

Some life-threatening acute hepatitis originates from drug-induced liver injury (DILI). Carbon tetrachloride (CCl)-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 specifically in liver parenchymal cells () or for the kinase activity of RIPK1 (, kinase dead), plus their respective wild-type littermates (, ), were exposed to single toxic doses of CCl. This exposure led in similar injury in mice and their littermate controls. However, 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 and mice. Besides, a FasL antagonist promoted hepatocyte apoptosis in mice but reduced it in mice. Thus, the scaffolding properties of RIPK1 protect hepatocytes from apoptosis during CCl 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.