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Our previous study reported a role of the pannexin 1 (PANX1)\u2013interleukin\u201033 (IL\u201033) axis in activating innate immunity to protect against methicillin\u2010resistant <jats:italic>Staphylococcus aureus<\/jats:italic> infection; however, the role of PANX1 in regulating adaptive immunity in sepsis and the underlying mechanism are unclear. In this study, we examined the role of the PANX1\u2013IL\u201033 axis in protecting against sepsis caused by a gram\u2010negative bacterial infection in an independent LT cohort. Next, in animal studies, we assessed the immunological state of Panx1<jats:sup>\u2212\/\u2010<\/jats:sup> mice with lipopolysaccharide (LPS)\u2010induced endotoxemia and then focused on the cytokine storm and regulatory T cells (Tregs), which are crucial for the resolution of inflammation. To generate liver\u2010specific Panx1\u2010deficient mice and mimic clinical LT procedures, a mouse LT model was established. We demonstrated that hepatic PANX1 deficiency exacerbated LPS\u2010induced endotoxemia and dysregulated the immune response in the mouse LT model. In hepatocytes, we confirmed that PANX1 positively regulated IL\u201033 synthesis after LPS administration. We showed that the adenosine triphosphate\u2010P2X7 pathway regulated the hepatic PANX1\u2013IL\u201033 axis during endotoxemia <jats:italic>in\u00a0vitro<\/jats:italic> and <jats:italic>in\u00a0vivo<\/jats:italic>. Recombinant IL\u201033 treatment rescued LPS\u2010induced endotoxemia by increasing the numbers of liver\u2010infiltrating ST2<jats:sup>+<\/jats:sup> Tregs and attenuating the cytokine storm in hepatic PANX1\u2010deficient mice. In conclusion, our findings revealed that the hepatic PANX1\u2013IL\u201033 axis protects against endotoxemia and liver injury by targeting ST2<jats:sup>+<\/jats:sup> Tregs and promoting the early resolution of hyperinflammation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.849","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T09:23:01Z","timestamp":1653038581000},"source":"Crossref","is-referenced-by-count":23,"title":["Hepatic pannexin\u20101 mediates ST2<sup>+<\/sup> regulatory T cells promoting resolution of inflammation in <i>lipopolysaccharide<\/i>\u2010induced endotoxemia"],"prefix":"10.1002","volume":"12","author":[{"given":"Pusen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery, Shanghai General Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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