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

摘要 干扰素基因刺激因子（stimulator of interferon genes，STING）是一种环二核苷酸（cyclic dinucleotides，CDN）的细胞质传感器，在细胞内起着至关重要的作用 作为许多细胞内DNA受体的衔接分子。上游的DNA传感器 包括环GMP-AMP合酶（cGAS）、IFN诱导蛋白和DExD/H-box解旋酶 家族蛋白，突出了STING在控制多种DNA识别途径中的重要功能。 STING在宿主防御病毒、细菌和真核病原体中是至关重要的，并且也对宿主的免疫系统起着重要作用。 自身免疫性疾病的发展。在这种防御机制中的滥用可以支持一系列 疾病，包括癌症和自身炎症性疾病。因此，STING是一个非常有前途的药物靶点。 最近的研究强调了STING在调节肠道炎症和肿瘤发生中的作用。作为 高水平的微生物来源的DNA和CDN存在于肠道中，这些刺激可能有助于局部 稳定状态下STING的激活。据报道，蜇伤-/-小鼠在急性结肠炎后发生更严重的结肠炎。 煽动性的侮辱我们的初步数据表明，T细胞表达STING的水平高于 树突状细胞（DCs）此外，STING信号传导的激活促进了T细胞产生IL-10和IL-20。 22但抑制IL-17的产生，表明STING可能潜在地调节肠道稳态和结肠炎。 通过促进抗炎性IL-10/IL-22和抑制促炎性细胞因子的产生， T细胞。在本申请中，我们将测试STING是否通过诱导T细胞产生IL-10和IL-22来促进T细胞产生IL-10和IL-22。 IRF 4和AHR表达由T细胞和树突状细胞产生I型IFN介导， 将导致肠道免疫稳态的保持和IBD的抑制。此外，我们将测试 STING激动剂是否可以预防和治疗结肠炎。

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.