Hepatocyte death induces TRIF-mediated sterile inflammation in the liver

Abstract

Abstract Hepatocyte death occurs as a result of infection, such as with hepatitis B and C viruses, and as a result of non-pathogen insults, such as chronic alcohol abuse, ischemia reperfusion injury, and acetaminophen overdose. The manner in which liver-specific cell populations—hepatocytes, resident macrophage Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs)—respond to this death is critical to understand as the resulting immune response often results not in resolution, but in enhanced liver inflammation that can ultimately lead to fibrosis and cirrhosis. Using an adeno-associated virus vector (AAV) encoding the human diphtheria toxin receptor (hDTR), we have created a murine model of hepatocyte-specific death. After administration of diphtheria toxin (DT), we see peak liver damage at 48 hours, as measured by serum alanine aminotransferase (ALT) levels. This response is largely controlled by TIR-domain-containing adapter-inducing interferon-β (TRIF), independent of both Toll-like receptor 4 (TLR4) and Interferon alpha/beta receptor (IFNAR), and is characterized by the up-regulation of Ifn-beta in hepatocytes by 24 hours and the up-regulation of both monocyte- and neutrophil-recruiting chemokines from hepatocytes, LSECs, and KCs most strongly by 48 hours. We see TRIF-dependent up-regulation of adhesion molecules (Vcam1 and Icam1) on hepatocytes and LSECs and down-regulation of MHC-II on the surface of KCs. Understanding how the TRIF pathway controls responses to hepatocyte death provides an intriguing counterpoint when compared to other models of liver death—such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and ischemia reperfusion injury—which occur via MyD88-dependent routes.