Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice
Department of Medicine, Division of Gastroenterology; Department of Medicine, Division of Infectious Diseases and Immunology
Digestive System Diseases | Gastroenterology | Hepatology | Immunity | Immunopathology
BACKGROUND and AIMS: The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1beta 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-1beta. 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-1beta 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.
Alcoholic steatohepatitis, Damage-associated molecular patterns, Determinants of liver inflammation, Inflammasome, Pathogen-associated molecular patterns, Sterile inflammatory response
DOI of Published Version
J Hepatol. 2015 Nov;63(5):1147-55. doi: 10.1016/j.jhep.2015.06.013. Epub 2015 Jun 20. Link to article on publisher's site
Journal of hepatology
Iracheta-Vellve, Arvin; Petrasek, Jan; Satishchandran, Abhishek; Gyongyosi, Benedek; Saha, Banishree; Kodys, Karen; Fitzgerald, Katherine A.; Kurt-Jones, Evelyn A.; and Szabo, Gyongyi, "Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice" (2015). University of Massachusetts Medical School Faculty Publications. 884.