Purinergic P2Y(2) Receptors Promote Neutrophil Infiltration and Hepatocyte Death in Mice With Acute Liver Injury

Background & Aims: During progression of liver disease, inflammation affects survival of hepatocytes. Endogenous release of adenosine triphosphate (ATP) in the liver activates purinergic P2 receptors (P2R), which regulate inflammatory responses, but little is known about the roles of these processes in the development of acute hepatitis. Methods: We induced acute hepatitis in C57BL/6 mice by intravenous injection of concanavalin A and then analyzed liver concentrations of ATP and expression of P2R. We assessed P2Y2R -/- mice and C57BL/6 wild-type mice injected with suramin, a pharmacologic inhibitor of P2YR. Toxic liver failure was induced in mice by intraperitoneal injection of acetaminophen. Hepatocyte-specific functions of P2R signaling were analyzed in primary mouse hepatocytes. Results: Induction of acute hepatitis in wild-type C57BL/6 mice released large amounts of ATP from livers and induced expression of P2Y2R. Liver damage and necrosis were greatly reduced in P2Y2R-/- mice and C57BL/6 mice given injections of suramin. Acetaminophen-induced liver damage was reduced in P2Y2R-/- mice. Analysis of liver-infiltrating immune cells during acute hepatitis revealed that expression of P2Y2R in bone marrow-derived cells was required for liver infiltration by neutrophils and subsequent liver damage. Hepatic expression of P2Y2R interfered with expression of genes that regulate cell survival, and promoted tumor necrosis factor-α-mediated cell death, in a cell-autonomous manner. Conclusions: Extracellular ATP and P2Y2R have cell-type specific, but synergistic functions during liver damage that regulate cellular immune responses and promote hepatocyte death. Reagents designed to target P2Y2R might be developed to treat inflammatory liver disease.