4.8 Article

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

期刊

出版社

JOHN WILEY & SONS LTD
DOI: 10.1002/ctm2.849

关键词

ATP; endotoxemia; IL-33; Panx1; Tregs

资金

  1. Natural Science Foundation of Shanghai [20ZR1445500]
  2. National Natural Science Foundation of China [82070672]

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This study revealed that the PANX1-IL-33 axis protects the liver from endotoxemia and injury by regulating T cells and early resolution of inflammation.
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.

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