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IRE1a silences double stranded RNA through RIDD

ABSTRACT: Chemotherapy is often combined with immune checkpoint inhibitor (ICI) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers including triple-negative breast cancer (TNBC), immunologically cold tumors remain largely unresponsive due to weak chemotherapy-stimulated immune responses. The mechanisms determining the immunogenicity of chemotherapy in immunologically cold tumors remain largely unknown. Here, we identify the endoplasmic reticulum (ER) stress sensor IRE1α as a critical checkpoint that restricts the immunogenicity of taxane chemotherapy and prevents the innate immune recognition of immunologically cold TNBC. IRE1α RNase silences chemotherapy-induced double-stranded RNA (dsRNA) through RIDD (Regulated IRE1-Dependent Decay) to prevent NLRP3 inflammasome–dependent pyroptosis. Inhibition of IRE1α RNase activity with a selective RNase inhibitor ORIN1001, currently in Phase I clinical trial, allows taxane chemotherapy to induce extensive dsRNA accumulation and activate NLRP3 inflammasome–dependent gasdermin D (GSDMD) cleavage. This triggers pyroptosis and a highly effective immune response in immunologically cold TNBC.

ORGANISM(S): Mus musculus

PROVIDER: GSE220315 | GEO | 2024/10/16

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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IRE1a silences double stranded RNA through RIDD

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