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

Abstract

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.

Implications of regulatory T cells in non-lymphoid tissue physiology and pathophysiology

“…Importantly, and unlike e.g., muscle or brain tissue Treg cells ( 106), Treg cell-mediated hepatic tissue protection was amphiregulin-independent, highlighting the context dependence of Treg cell-mediated tissue repair. Finally, a recent study has implicated the IL-33/ ST2 axis in the resolution of heightened hepatic inflammation in the context of LPS-induced sepsis (127), namely that IL-33 released from injured liver cells recruits ST2 + Treg cells, which then facilitate the resolution of inflammation.…”

Hepatic pannexin‐1 controls interleukin‐33 synthesis and release via the ATP‐P2X7 pathway with clinical implications for the resolution of hyperinflammation in sepsis

“…In a recent manuscript published in Clinical and Translational Medicine, 7 Wang et al. describe a new role for the pannexin‐1/IL‐33 axis in alleviating liver damage during lipopolysaccharide (LPS)‐induced endotoxemia.…”

“…Pannexin-1-dependent differences in hepatic damage and resolution of inflammation during lipopolysaccharide (LPS) endotoxemia as described in Wang et al 7 Given their promising clinical observations pertinent to the protective role of pannexin-1 in sepsis, the authors next examined whether pannexin-1 deficiency may causatively affect LPS-induced endotoxemia and liver injury in vivo. Indeed, pannexin-1-knockout (Panx1 -/-) mice showed more extensive liver damage, and increased mortality after intraperitoneal LPS administration compared to wild-type (WT) mice.…”

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Pannexin-1-dependent differences in hepatic damage and resolution of inflammation during lipopolysaccharide endotoxemia as described in Wang et al 7

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“…6 Of note, sepsis-surviving patients have more Tregs and IL-33, but lower soluble IL-33 receptors, namely ST2, in their peripheral blood. 5,6 In a recent manuscript published in Clinical and Translational Medicine, 7 Wang et al describe a new role for the pannexin-1/IL-33 axis in alleviating liver damage during lipopolysaccharide (LPS)-induced endotoxemia. The authors focused on liver transplant recipients, as a highrisk group for sepsis development.…”