title: Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Arvin
authors.initials: A
authors.lastname: Iracheta-Vellve
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Petrasek
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Satishchandran
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Benedek
authors.initials: B
authors.lastname: Gyongyosi
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Banishree
authors.initials: B
authors.lastname: Saha
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: gyongyi.szabo@umassmed.edu.
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000277:Adjuvants, Pharmaceutic / Q000627:therapeutic use; D000493:Allopurinol / Q000627:therapeutic use*; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D011339:Probenecid / Q000627:therapeutic use*; D015398:Signal Transduction; D014527:Uric Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000277:Adjuvants, Pharmaceutic; D000963:Antimetabolites; D058847:Inflammasomes; D014527:Uric Acid; D000493:Allopurinol; D000255:Adenosine Triphosphate; D011339:Probenecid
keywords: Alcoholic steatohepatitis; Damage-associated molecular patterns; Determinants of liver inflammation; Inflammasome; Pathogen-associated molecular patterns; Sterile inflammatory response