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

J Hepatol. 2015 Nov;63(5):1147-55. doi: 10.1016/j.jhep.2015.06.013. Epub 2015 Jun 20.


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.

Keywords: Alcoholic steatohepatitis; Damage-associated molecular patterns; Determinants of liver inflammation; Inflammasome; Pathogen-associated molecular patterns; Sterile inflammatory response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / antagonists & inhibitors*
  • Adenosine Triphosphate / metabolism
  • Adjuvants, Pharmaceutic / therapeutic use
  • Allopurinol / therapeutic use*
  • Animals
  • Antimetabolites / therapeutic use
  • Cells, Cultured
  • Disease Models, Animal
  • Fatty Liver, Alcoholic / drug therapy
  • Fatty Liver, Alcoholic / metabolism*
  • Fatty Liver, Alcoholic / pathology
  • Female
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Inflammasomes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Probenecid / therapeutic use*
  • Signal Transduction
  • Uric Acid / antagonists & inhibitors*
  • Uric Acid / metabolism


  • Adjuvants, Pharmaceutic
  • Antimetabolites
  • Inflammasomes
  • Uric Acid
  • Allopurinol
  • Adenosine Triphosphate
  • Probenecid