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Hedgehog Induced ZFYVE21 Activates T Cell Intrinsic, NLRP3 Inflammasomes to Promote Chronic Inflammation

ABSTRACT: ZFYVE21 is a novel Rab5 effector involved in immune signaling whose functions in vivo are undefined. Using humanized mouse models and patient specimens, we describe a T cell-autonomous role for ZFYVE21 in promoting chronic inflammation. Following ischemia reperfusion injury (IRI), endothelial cells (ECs) produce Hedgehog (Hh) ligands. Hh ligands induce expression of ZFYVE21 in a “Ptchhi” cell population (CD3+CD4+CD45RO+Ptch1hiPD-1hi) that is highly responsive to Hh signaling and which display vigorous EC-mediated recruitment and effector responses in vivo. Mechanistically, following IFN-gamma-dependent priming, Hh-induced ZFYVE21 modulates T cell intrinsic, NLRP3 inflammasome activity in an Akt-dependent manner to allow IL-18-mediated potentiation of IFN-gamma responses. Hh-induced NLRP3 inflammasomes and T cell-specific ZFYVE21 augment vascular sequelae of chronic inflammation. Moreover, Ptchhi T cells highly expressing ZFYVE21 are expanded in IRI patients, and frequencies of these cells are modulated by Hh signaling. Hh-induced ZFYVE21 activates T cell intrinsic, NLRP3 inflammasomes to promote chronic inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE208349 | GEO | 2022/07/22

REPOSITORIES: GEO

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Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

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Hedgehog Induced ZFYVE21 Activates T Cell Intrinsic, NLRP3 Inflammasomes to Promote Chronic Inflammation

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