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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.

SUBMITTER: Wang P

PROVIDER: S-EPMC9121315 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Hepatic pannexin-1 mediates ST2<sup>+</sup> regulatory T cells promoting resolution of inflammation in lipopolysaccharide-induced endotoxemia.

Wang Pusen P Shi Baojie B Wang Chunguang C Wang Yuanyuan Y Que Weitao W Jiang Zhongyi Z Liu Xueni X Jiang Qianwei Q Li Hao H Peng Zhihai Z Zhong Lin L

Clinical and translational medicine 20220501 5

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 prote ...[more]

PMID: 35593197

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Project description:Background & aimsHepatic stellate cells (HSCs) contribute to desmoplasia and stiffness of liver metastases by differentiating into matrix-producing myofibroblasts. We investigated whether stiffness due to the presence of tumors increases activation of HSCs into myofibroblasts and their tumor-promoting effects, as well as the role of E1A binding protein p300, a histone acetyltransferase that regulates transcription, in these processes.MethodsHSCs were isolated from liver tissues of patients, mice in which the p300 gene was flanked by 2 loxP sites (p300F/F mice), and p300+/+ mice (controls). The HSCs were placed on polyacrylamide gels with precisely defined stiffness, and their activation (differentiation into myofibroblasts) was assessed by immunofluorescence and immunoblot analyses for alpha-smooth muscle actin. In HSCs from mice, the p300 gene was disrupted by cre recombinase. In human HSCs, levels of p300 were knocked down with small hairpin RNAs or a mutant form of p300 that is not phosphorylated by AKT (p300S1834A) was overexpressed. Human HSCs were also cultured with inhibitors of p300 (C646), PI3K signaling to AKT (LY294002), or RHOA (C3 transferase) and effects on stiffness-induced activation were measured. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction were used to identify HSC genes that changed expression levels in response to stiffness. We measured effects of HSC-conditioned media on proliferation of HT29 colon cancer cells and growth of tumors following subcutaneous injection of these cells into mice. MC38 colon cancer cells were injected into portal veins of p300F/Fcre and control mice, and liver metastases were measured. p300F/Fcre and control mice were given intraperitoneal injections of CCl4 to induce liver fibrosis. Liver tissues were collected and analyzed by immunofluorescence, immunoblot, and histology.ResultsSubstrate stiffness was sufficient to activate HSCs, leading to nuclear accumulation of p300. Disrupting p300 level or activity blocked stiffness-induced activation of HSCs. In HSCs, substrate stiffness activated AKT signaling via RHOA to induce phosphorylation of p300 at serine 1834; this caused p300 to translocate to the nucleus, where it up-regulated transcription of genes that increase activation of HSCs and metastasis, including CXCL12. MC38 cells, injected into portal veins, formed fewer metastases in livers of p300F/Fcre mice than control mice. Expression of p300 was increased in livers of mice following injection of CCl4; HSC activation and collagen deposition were reduced in livers of p300F/Fcre mice compared with control mice.ConclusionsIn studies of mice, we found liver stiffness to activate HSC differentiation into myofibroblasts, which required nuclear accumulation of p300. p300 increases HSC expression of genes that promote metastasis.

Dataset Information

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

Publications

Hepatic pannexin-1 mediates ST2<sup>+</sup> regulatory T cells promoting resolution of inflammation in lipopolysaccharide-induced endotoxemia.

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

Publications

Hepatic pannexin-1 mediates ST2<sup>+</sup> regulatory T cells promoting resolution of inflammation in lipopolysaccharide-induced endotoxemia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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