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Although hepatocytes, produce IL\u201036 responses to drug\u2010induced liver injury, little is known about the mechanistic role of IL\u201036 signalling during the progression of alcoholic steatohepatitis (ASH). Regarding IL\u201036\/IL\u201036R and P2X7R coregulating the inflammatory response, we elucidated that modulation of IL\u201036R\u2010P2X7R\u2010TLR axis affected hepatocyte steatosis as well as the IL\u201036\u2010based inflammatory feedback loop that accompanies the onset of ASH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>C57BL\/6J mice were subjected to either chronic\u2010plus\u2010binge ethanol feeding or acute gavage with multiple doses of ethanol to establish ASH, followed by pharmacological inhibition or genetic silencing of IL\u201036R and P2X7R. AML12 cells or mouse primary hepatocytes were stimulated with alcohol, LPS plus ATP or Poly(I:C) plus ATP, followed by silencing of IL\u201036\u03b3, IL\u201036R or P2X7R.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>P2X7R and IL\u201036R deficiency blocked the inflammatory loop, specifically initiated by IL\u201036 cytokines, in hepatocytes of mice suffering from ASH. Pharmacological inhibition to P2X7R or IL\u201036R alleviated lipid accumulation and inflammatory response in ASH. IL\u201036R was indispensable for P2X7R modulated NLRP3 inflammasome activation in ASH, and IL\u201036 led to a vicious cycle of P2X7R\u2010driven inflammation in alcohol\u2010treated hepatocytes. TLR ligands promoted IL\u201036\u03b3 production in hepatocytes, based on synergism with P2X7R.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Blockade of IL\u201036 based inflammatory feedback loop, via IL\u201036R\u2010P2X7R\u2010TLRs\u2010modulated NLRP3 inflammasome activation, circumvented steatosis and inflammation that accompanies the onset of ASH, suggesting that targeting IL\u201036 can serve as a novel therapeutic approach to combat ASH.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15858","type":"journal-article","created":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T13:38:10Z","timestamp":1651153090000},"page":"4378-4399","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Modulation of interleukin\u201036 based inflammatory feedback loop through the hepatocyte\u2010derived IL\u201036R\u2010P2X7R axis improves steatosis in alcoholic 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