STING signaling in T cells regulation of intestinal homeostasis and inflammatorybowel diseases

摘要 STING（干扰素基因刺激剂）是一种环状二核苷酸 (CDN) 细胞质传感器，发挥着至关重要的作用 作为许多细胞内 DNA 受体的接头分子。发出信号的上游 DNA 传感器 通过 STING 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、细菌和真核病原体方面发挥着至关重要的作用，对于 自身免疫性疾病的发展。这种防御机制的异常可能会导致一系列的问题 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 肠道中存在高水平的微生物群衍生的 DNA 和 CDN，这些刺激可能有助于局部 稳定状态下 STING 的激活。据报道，Sting-/-小鼠在急性发作后会出现更严重的结肠炎。 炎症性侮辱。我们的初步数据表明，T 细胞表达 STING 的水平高于 在树突状细胞（DC）中。此外，STING 信号传导的激活促进了 T 细胞产生 IL-10 和 IL- 22 但抑制 IL-17 的产生，表明 STING 可能调节肠道稳态和结肠炎 通过促进抗炎 IL-10/IL-22 和抑制促炎细胞因子的产生来促进发育 T细胞。在此应用中，我们将测试 STING 是否通过诱导 T 细胞促进 IL-10 和 IL-22 的产生 IRF4 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.