Specific Bile Acids Elicit the Type-I Interferon Response Through the cGAS-STING Pathway 2329596

Abstract Introduction Bile acids are metabolites crucially involved in lipid metabolism and immune regulation. Despite the recent identification of enormous bile acids differing in composition, their biological functions and mechanistic underpinnings remain largely elusive. Methods In this study, we demonstrate that specific bile acids DCA, CDCA and LCA are capable of triggering the type-I interferon response (IFN-I) in various cells, including colonic epithelial cells, macrophages and fibroblasts. Genetic and pharmacologic analyses revealed that these three bile acids impinged on a common IFN-I-inducing cGAS-STING pathway, whose activation associated with the cytosolic release of mitochondrial DNAs. Phosphoproteomics indicated that DCA treatment led to a wide array of changes across numerous signaling pathways, including TBK1-IRF3, AKT-mTOR, PKA-BAD and CaMKII-NFAT. Results The downregulation of Bcl-2 abundance and BAD phosphorylation coincided with the formation of Bax/Bak foci on the mitochondrial membrane. Chemical blockade or genetic knockdown of Bax/Bak diminished DCA-induced Ifnb1 expression, revealing a crucial role of Bax/Bak pore in mtDNA release. The induction of the IFN-I response also depended on inter-organelle interactions among the endolysosome, ER and mitochondria, as cholesterol-dependent endocytosis and ER-derived calcium flux promoted DCA’s ability to induce the IFN-I response. Further, intraperitoneally administered DCA elicited the IFN-I response in various organs and tissues contingent on the STING pathway. Conclusion Together, these findings identify the cGAS-STING pathway as a mechanistic underpinning of specific bile acids and provide new insights into therapeutic interventions for bile acid-related pathologies. Funding Source The National Natural Science Foundation of China Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)