Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice

Arvin Iracheta-Vellve, Jan Petrasek, Abhishek Satishchandran, Benedek Gyongyosi, Banishree Saha, Karen Kodys, Katherine A. Fitzgerald, Evelyn A. Kurt-Jones, Gyongyi Szabo

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background & Aims The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1β production. Here we asked whether metabolic danger signals trigger inflammasome activation in ASH. Methods Wild-type mice, ATP receptor 2x7 (P2rx7)-KO mice, or mice overexpressing uricase were fed Lieber-DeCarli ethanol or control diet. We also implemented a pharmacological approach in which mice were treated with probenecid or allopurinol. Results The sterile danger signals, ATP and uric acid, were increased in the serum and liver of alcohol-fed mice. Depletion of uric acid or ATP, or lack of ATP signaling attenuated ASH and prevented inflammasome activation and its major downstream cytokine, IL-1β. Pharmacological depletion of uric acid with allopurinol provided significant protection from alcohol-induced inflammatory response, steatosis and liver damage, and additional protection was achieved in mice treated with probenecid, which depletes uric acid and blocks ATP-induced P2rx7 signaling. We found that alcohol-damaged hepatocytes released uric acid and ATP in vivo and in vitro and that these sterile danger signals activated the inflammasome in LPS-exposed liver mononuclear cells. Conclusions Our data indicate that the second signal in inflammasome activation and IL-1β production in ASH results from the endogenous danger signals, uric acid and ATP. Inhibition of signaling triggered by uric acid and ATP may have therapeutic implications in ASH.

Original languageEnglish
Pages (from-to)1147-1155
Number of pages9
JournalJournal of Hepatology
Volume63
Issue number5
DOIs
Publication statusPublished - Nov 2015

Keywords

  • Alcoholic steatohepatitis
  • Damage-associated molecular patterns
  • Determinants of liver inflammation
  • Inflammasome
  • Pathogen-associated molecular patterns
  • Sterile inflammatory response

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice'. Together they form a unique fingerprint.

  • Cite this

    Iracheta-Vellve, A., Petrasek, J., Satishchandran, A., Gyongyosi, B., Saha, B., Kodys, K., Fitzgerald, K. A., Kurt-Jones, E. A., & Szabo, G. (2015). Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice. Journal of Hepatology, 63(5), 1147-1155. https://doi.org/10.1016/j.jhep.2015.06.013