Hepatic pannexin‐1 mediates ST2+ regulatory T cells promoting resolution of inflammation in lipopolysaccharide‐induced endotoxemia

Sepsis remains the most lethal infectious disease and substantially impairs patient prognosis after liver transplantation (LT). Our previous study reported a role of the pannexin 1 (PANX1)–interleukin‐33 (IL‐33) axis in activating innate immunity to protect against methicillin‐resistant Staphylococcus aureus 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–IL‐33 axis in protecting against sepsis caused by a gram‐negative bacterial infection in an independent LT cohort. Next, in animal studies, we assessed the immunological state of Panx1−/‐ mice with lipopolysaccharide (LPS)‐induced endotoxemia and then focused on the cytokine storm and regulatory T cells (Tregs), which are crucial for the resolution of inflammation. To generate liver‐specific Panx1‐deficient mice and mimic clinical LT procedures, a mouse LT model was established. We demonstrated that hepatic PANX1 deficiency exacerbated LPS‐induced endotoxemia and dysregulated the immune response in the mouse LT model. In hepatocytes, we confirmed that PANX1 positively regulated IL‐33 synthesis after LPS administration. We showed that the adenosine triphosphate‐P2X7 pathway regulated the hepatic PANX1–IL‐33 axis during endotoxemia in vitro and in vivo. Recombinant IL‐33 treatment rescued LPS‐induced endotoxemia by increasing the numbers of liver‐infiltrating ST2+ Tregs and attenuating the cytokine storm in hepatic PANX1‐deficient mice. In conclusion, our findings revealed that the hepatic PANX1–IL‐33 axis protects against endotoxemia and liver injury by targeting ST2+ Tregs and promoting the early resolution of hyperinflammation. Pannexin 1 (PANX1) deficiency exacerbated lipopolysaccharide (LPS)‐induced endotoxemia and dysregulated the immune response. Adenosine triphosphate‐P2X7 pathway regulated the hepatic PANX1–interleukin‐33 (IL‐33)axis during endotoxemia. IL‐33 rescued LPS‐induced endotoxemia by increasing the numbers of liver‐infiltrating ST2+ Tregs and attenuating the cytokine storm.