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Abstract：
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-κB 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.
摘要：
原理：溃疡性结肠炎（UC）的治疗提出了持续的临床挑战。新兴研究暗示cGAS-STING途径促进UC的进展，但是矛盾的结果阻碍了STING作为治疗靶标的发展。在目前的研究中,我们旨在全面阐明其起源，髓样STING在结肠炎和结肠炎相关癌（CAC）中的下游信号传导和致病作用。方法：构建Tmem173fl/flLyz2-Creert2小鼠，用于诱导骨髓特异性缺失STING。RNA测序，流式细胞术,和多重免疫组织化学用于研究DSS诱导的结肠炎或AOM/DSS诱导的癌变中的免疫反应。结肠类器官,原代骨髓源性巨噬细胞和树突状细胞，和脾T细胞用于体外研究。结果：我们观察到成年小鼠的髓样STING敲除抑制巨噬细胞成熟，减少DC细胞激活，并抑制促炎Th1和Th17细胞，从而防止急性和慢性结肠炎和CAC。然而,新生小鼠或肿瘤小鼠的髓样STING缺失表现出受损的免疫耐受和抗肿瘤免疫力。此外，我们发现从受损的结肠类器官释放的TFAM相关mtDNA，而不是细菌产品，以细胞外囊泡非依赖性但内吞依赖性方式激活树突状细胞中的STING。IRF3和NF-κB都是STING介导的IL-12家族细胞因子表达所必需的，促进Th1和Th17分化，并有助于结肠炎的过度炎症。结论：通过髓样STING检测受损肠上皮的TFAM-mtDNA复合物可通过IL-12细胞因子加重结肠炎，提供新的证据支持STING作为UC和CAC的治疗靶点的发展。
