| First Author | Cai Y | Year | 2024 |
| Journal | Theranostics | Volume | 14 |
| Issue | 11 | Pages | 4393-4410 |
| PubMed ID | 39113810 | Mgi Jnum | J:352965 |
| Mgi Id | MGI:7708629 | Doi | 10.7150/thno.96184 |
| Citation | Cai Y, et al. (2024) Intestinal epithelial damage-derived mtDNA activates STING-IL12 axis in dendritic cells to promote colitis. Theranostics 14(11):4393-4410 |
| abstractText | Rationale: The treatment of ulcerative colitis (UC) presents an ongoing clinical challenge. Emerging research has implicated that the cGAS-STING pathway promotes the progression of UC, but conflicting results have hindered the development of STING as a therapeutic target. In the current study, we aim to comprehensively elucidate the origins, downstream signaling and pathogenic roles of myeloid STING in colitis and colitis-associated carcinoma (CAC). Methods: Tmem173 (fl/fl) Lyz2-Cre (ert2) mice were constructed for inducible myeloid-specific deletion of STING. RNA-sequencing, flow cytometry, and multiplex immunohistochemistry were employed to investigate immune responses in DSS-induced colitis or AOM/DSS-induced carcinogenesis. Colonic organoids, primary bone marrow derived macrophages and dendritic cells, and splenic T cells were used for in vitro studies. Results: We observed that myeloid STING knockout in adult mice inhibited macrophage maturation, reduced DC cell activation, and suppressed pro-inflammatory Th1 and Th17 cells, thereby protecting against both acute and chronic colitis and CAC. However, myeloid STING deletion in neonatal or tumor-present mice exhibited impaired immune tolerance and anti-tumor immunity. Furthermore, we found that TFAM-associated mtDNA released from damaged colonic organoids, rather than bacterial products, activates STING in dendritic cells in an extracellular vesicle-independent yet endocytosis-dependent manner. Both IRF3 and NF-kappaB are required for STING-mediated expression of IL-12 family cytokines, promoting Th1 and Th17 differentiation and contributing to excessive inflammation in colitis. Conclusions: Detection of the TFAM-mtDNA complex from damaged intestinal epithelium by myeloid STING exacerbates colitis through IL-12 cytokines, providing new evidence to support the development of STING as a therapeutic target for UC and CAC. |
