P2Y2 receptor function aggravates acute hepatitis by regulating neutrophil infiltration and hepatocyte survival

Background & Aims: Analysis of the molecular pathways linking inflammation and hepatocyte survival is essential to identify novel therapies for inflammatory liver disease. Release of extracellular ATP and subsequent activation of purinergic P2 receptors (P2R) is increasingly recognized as an important danger signal and mediator of pro-inflammatory responses. We therefore addressed the question whether ATP and P2R serve as major regulators of acute hepatitis. Methods: To address this issue, acute hepatitis was induced in P2R knockout mice and controls by injection of Concanavalin A, an established model of fulminant and TNFα-dependent hepatitis. Moreover, hepatocyte-specific functions of P2R signaling in response to TNFα were analyzed in primary mouse hepatocytes. Results: Induction of acute hepatitis in control animals resulted in a strong ATP release from the liver and marked induction of its receptor P2Y2R. Concanavalin A-mediated liver damage was dramatically reduced in wild type mice co-injected with the P2YR inhibitor Suramin as well as in P2Y2R^-/- mice. These livers were characterized by strikingly reduced neutrophil infiltration. In addition, cell death following treatment with TNFα and N-Galactosamine was reduced in primary hepatocytes lacking P2Y2R. Moreover, improved hepatocyte survival correlated with increased activation of NF-κB and subsequent transcription of hepatoprotective target genes including A20 and Birc5. Conclusions: These findings indicate that extracellular ATP and P2Y2R have cell type-specific but synergistic functions during acute hepatitis by regulating cellular immune responses as well as hepatocyte survival. Targeting of P2Y2R may therefore be a promising approach to treat inflammatory liver disease.

Extracellular ATP - purinergic receptors - Concanavalin A - hepatocyte apoptosis