The balance between apoptosis and proliferation represents the basis for the maintenance of tissue homeostasis. Receptor mediated cell death through the activation of Caspases has been identified as an important mechanism to control life and death in various tissues. In this study, we modulated Caspase-8 activity in individual liver cell types using hepatocyte-specific knockout mice for Caspase-8 (Casp8Deltahepa) and a mouse strain for a ubiquitous deletion of Caspase-8 (Casp8DeltaMx) in the DDC (3,5-diethocarbonyl-1,4-dihydrocollidine) model of secondary sclerosing cholangitis and liver progenitor cells (LPCs) activation. Here, we demonstrate that mice with Caspase-8 inhibition in hepatocytes (Casp8Deltahepa) were protected from DDC-mediated injury, while mice with a ubiquitous conditional Caspase-8 knockout (Casp8DeltaMx) displayed a significantly enhanced hepatic inflammation and tissue injury. This was demonstrated by higher transaminases, bilirubin levels and finally also more liver fibrosis. Thereby Caspase-3 activity was reduced in both knockout strains, suggesting other mechanisms being responsible for the phenotype. Correlating with enhanced liver injury, Casp8DeltaMx mice displayed a stronger infiltration of mononuclear immune cells and more proliferation of LPCs in periportal areas. Further analysis confirmed that these infiltrating immune cells are resistant against extrinsic apoptosis. Bone marrow transplantation (BMT) experiments demonstrated that Caspase-8-deficient bone marrow derived cells are responsible for increased liver injury in DDC fed mice. Taken together, our in vitro and in vivo finding demonstrates a cell-specific and distinct impact of Caspase-8 on individual liver cell types. While a hepatocyte specific knockout provided protection from liver damage the ubiquitous deletion of Caspase-8 triggered more injury and inflammation. This phenotype was associated with a stronger ductular reaction and activation of the hepatic progenitor cell niche and caused through mechanism of immune-cell mediated liver injury
