title: Purinergic P2Y₂ receptors promote neutrophil infiltration and hepatocyte death in mice with acute liver injury.
abstract: OBJECTIVE
  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 P2Y(2)R(-/-) 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 P2Y(2)R. Liver damage and necrosis were greatly reduced in P2Y(2)R(-/-) mice and C57BL/6 mice given injections of suramin. Acetaminophen-induced liver damage was reduced in P2Y(2)R(-/-) mice. Analysis of liver-infiltrating immune cells during acute hepatitis revealed that expression of P2Y(2)R in bone marrow-derived cells was required for liver infiltration by neutrophils and subsequent liver damage. Hepatic expression of P2Y(2)R 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 P2Y(2)R have cell-type specific, but synergistic functions during liver damage that regulate cellular immune responses and promote hepatocyte death. Reagents designed to target P2Y(2)R might be developed to treat inflammatory liver disease.
authors.affiliation: Department of Medicine V, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Cemil Korcan
authors.initials: CK
authors.lastname: Ayata
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Ganal
authors.forename: Birgit
authors.initials: B
authors.lastname: Hockenjos
authors.forename: Karolina
authors.initials: K
authors.lastname: Willim
authors.forename: Rodolfo P
authors.initials: RP
authors.lastname: Vieira
authors.forename: Melanie
authors.initials: M
authors.lastname: Grimm
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pellegatti
authors.forename: Andreas
authors.initials: A
authors.lastname: Diefenbach
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.forename: Peter
authors.initials: P
authors.lastname: Hasselblatt
mesh_terms: D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003208:Concanavalin A / Q000009:adverse effects; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000473:pathology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000502:physiology*; D058473:Receptors, Purinergic P2Y2 / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology
chemical_list: D058473:Receptors, Purinergic P2Y2; D003208:Concanavalin A; D013498:Suramin; D000255:Adenosine Triphosphate