Biography
Biography: Samson Michel
Abstract
Hepatocyte death is a starting point of liver disease progression by promoting inflammatory and regenerative processes. The death of hepatocytes can be induced by the large variety of immune, infectious and toxic agents. When the hepatocyte death becomes chronic, a development of fibrosis, cirrhosis or hepatocellular carcinoma occur. The molecular mechanisms regulating these cell death pathways are poorly documented. Innate and acquired immune cells play key roles in the induction or amplification of hepatolysis, mainly mediated by expression and release of death ligands belonging to the TNF-superfamily including TNF-α, FasL and TRAIL. In this study, we investigated the role of RIPK1, a protein known to regulate cell fate decisions, in the death of hepatocytes using different in vivo models of hepatitis. Hepatitis was induced in mice by Concanavalin A (ConA), lipopolysaccharide (LPS), DNA-CpG, recombinant IFN-γ and TRAIL co-administration, FASL, Poly I:C, Murine-Hepatitis virus type 3, and high fat diet. Using specific conditional mice deficient in RIPK1 only in liver parenchymal cells (LPC) (Ripk1LPC-KO), we reveal its necessary function in the protection of hepatocyte during hepatitis. Administration of lipsome-encapsulated Cl2MBP served to investigate the role of Kupffer cells in the establishment of the disease. Moreover, Etanercept, a TNF-decoy receptor, was used to study the contribution of TNF-α during liver injury. All together, these works demonstrate that deletion of RIPK1 sensitizes hepatocytes to TNF-α-induced apoptosis. Thus RIPK1 plays a key role in the protection of hepatocytes during acute and chronic hepatitis.