STING signaling in T cells regulation of intestinal homeostasis and inflammatory bowel diseases

摘要 SING(干扰素基因刺激物)是环状二核苷酸(Cdns)的细胞质感受器，在生物体内起着至关重要的作用。 作为一种细胞内DNA受体的适配器分子。上游的DNA传感器发出信号 包括环状GMP-AMP合成酶(CGAS)、干扰素诱导蛋白和DExD/H-box解旋酶 家族蛋白，突出了STING在控制多个DNA识别途径中的重要功能。 在抵御病毒、细菌和真核病原体的宿主防御中，刺痛一直是至关重要的，对 自身免疫性疾病的发展。这种防御机制中的异常可以支持一系列 疾病，包括癌症和自身炎症性疾病。因此，斯汀是一个非常有希望的药物靶点。 最近的研究强调了刺痛在调节肠道炎症和肿瘤发生中的作用。AS 肠道中存在高水平的微生物衍生DNA和CDN，这些刺激可能有助于局部 稳定状态下的刺激性。据报道，被叮咬的小鼠在急性结肠炎后会发展成更严重的结肠炎。 煽动性侮辱。我们的初步数据显示，T细胞表达STIN的水平高于 在树突状细胞(DC)中。此外，STING信号的激活促进了T细胞产生IL-10和IL-2 22但抑制IL-17的产生，表明刺痛可能潜在地调节肠道内环境平衡和结肠炎 促进抗炎IL-10/IL-22和抑制促炎细胞因子产生的研究进展 T细胞。在这个应用中，我们将测试STIN是否通过诱导T细胞产生IL-10和IL-22 IRF4和AHR的表达是由T细胞和树突状细胞产生I型IFN介导的 可维持肠道免疫动态平衡，抑制IBD。此外，我们还将测试 刺激剂是否能预防和治疗结肠炎。

ABSTRACT STING (stimulator of interferon genes), a cytoplasmic sensor for cyclic dinucleotides (CDNs), plays a crucial role as an adaptor molecule for a number of intracellular DNA receptors. The upstream DNA sensors that signal through STING include cyclic GMP-AMP synthase (cGAS), IFN-inducible proteins, and DExD/H-box helicase family proteins, highlighting an important function for STING in controlling multiple DNA recognition pathways. STING has been crucial in host defense against viral, bacterial, and eukaryotic pathogens, and also to the development of autoimmune disease. Abnormalities in this defense mechanism can underpin a spectrum of conditions, including cancer and autoinflammatory diseases. STING is thus a highly promising drug target. Recent studies have underscored the role of STING in regulating intestinal inflammation and tumorigenesis. As high levels of microbiota-derived DNA and CDNs are present in the gut, these stimuli could contribute to local activation of STING at steady state. Sting-/- mice have been reported to develop more severe colitis upon acute inflammatory insult. Our preliminary data demonstrated that T cells expressed STING at levels higher than that in dendritic cells (DCs). Furthermore, activation of STING signaling promoted T cell production of IL-10 and IL- 22 but inhibited IL-17 production, indicating that STING may potentially regulate intestinal homeostasis and colitis development by promoting anti-inflammatory IL-10/IL-22 and inhibiting proinflammatory cytokine production by T cells. In this application, we will test whether STING promotes T cell production of IL-10 and IL-22 by inducing IRF4 and AHR expression mediated by the production of type I IFNs by both T cells and dendritic cells, which would lead to the preservation of intestinal immune homeostasis and inhibition of IBD. Furthermore, we will test whether STING agonists can prevent and treat colitis.