Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells

• Published in: Immunity (Cambridge, Mass.) Mass.), 2021-06, Vol.54 (6), p.1137-1153.e8
• Main Authors: Shmuel-Galia, Liraz, Humphries, Fiachra, Lei, Xuqiu, Ceglia, Simona, Wilson, Ruth, Jiang, Zhaozhao, Ketelut-Carneiro, Natalia, Foley, Sage E., Pechhold, Susanne, Houghton, JeanMarie, Muneeruddin, Khaja, Shaffer, Scott A., McCormick, Beth A., Reboldi, Andrea, Ward, Doyle, Marshak-Rothstein, Ann, Fitzgerald, Katherine A.
• Format: Article
• Language: English
• Subjects: Accumulation; Adapter proteins; Bacteria; Bone marrow; Colitis; Colon; commensal; Deoxyribonucleic acid; Depletion; DNA; Dysbacteriosis; dysbiosis; Feedback loops; Fibrosis; Gram-negative bacteria; Homeostasis; Inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; intestinal inflammation; Intestine; Lymphocytes; Macrophages; microbiome; Monocytes; Mutation; Myeloid cells; Positive feedback; Post-translation; Protein expression; Roles; Salmonella; SAVI; STING; Transcription; Ubiquitination
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.05.008

Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease. Mice bearing an allele rendering STING constitutively active exhibited spontaneous colitis and dysbiosis, as well as progressive chronic intestinal inflammation and fibrosis. Bone marrow chimera experiments revealed STING accumulation in intestinal macrophages and monocytes as the initial driver of inflammation. Depletion of Gram-negative bacteria prevented STING accumulation in these cells and alleviated intestinal inflammation. STING accumulation occurred at the protein rather than transcript level, suggesting post-translational stabilization. We found that STING was ubiquitinated in myeloid cells, and this K63-linked ubiquitination could be elicited by bacterial products, including cyclic di-GMP. Our findings suggest a positive feedback loop wherein dysbiosis foments the accumulation of STING in intestinal myeloid cells, driving intestinal inflammation. [Display omitted] •Constitutive activation of STING initiates commensal dysbiosis•STING accumulates predominantly in intestinal myeloid cells during colitis•STING activation in myeloid cells results in progressive and chronic colitis•Colitis-promoting bacterial products trigger ubiquitination and stabilization of STING To understand the function of the DNA sensing protein STING in intestinal inflammation, Shmeul-Galia et al. utilize a constitutively active STING mouse model that exhibits dysbiosis, severe colitis, and fibrosis. Bacterial nucleotides like cyclic di-GMP initiate a feed-forward loop through the ubiquitination and stabilization of STING in intestinal myeloid cells to promote T cell-dependent colitis.