Mechanisms of STING-driven autoinflammation

环状GMP-AMP合成酶(CGAS)检测感染过程中的外来DNA或导致自身DNA Aicardi-Goutieres综合征等自身炎症性疾病。CGAS信号通过SING，一种循环受体 GMP-cGAS生成的AMP。一系列功能获得突变导致的结构性激活 刺痛与一种名为刺痛相关的衰弱自体炎症疾病有关- 起病于婴儿期的血管病(SAVI)。SAVI患者有严重的血管炎性病变和间质病变 肺部疾病(ILD)，并经常死于呼吸衰竭。就像与其他疾病相关的肺部疾病 自身免疫性疾病，如类风湿性关节炎和系统性硬化症，对 促进这些患者发炎的机制。为了深入了解刺痛驱动的机制 在肺部炎症方面，我们建立了一种最常见的SAVI突变STINGV154M的小鼠模型 (Vm)，并发现该突变杂合子的小鼠会出现免疫异常和肺部疾病。肺 根据我们的初步数据，内皮细胞是肺中表达刺激物最高的细胞之一 我们认为，VM肺中的自体炎症是SAVI突变对“启动者”的直接影响所致。 抗辐射细胞(内皮细胞和/或成纤维细胞)导致基质细胞激活，分化， 趋化因子的生产和扩张。然后，淋巴细胞(VM或WT)被招募到肺中。招聘人员 效应T细胞进一步促进辐射抵抗细胞和髓系细胞的致病活性，导致 慢性炎症；干扰素在这一过程中起着关键作用。VM SAVI等位基因是如何介导疾病的 间质细胞的发病机制尚不清楚。我们将专注于内皮细胞中的刺激性激活以及如何 这些事件导致淋巴细胞的募集、激活和病理。目标1将确定淋巴细胞- SAVI基因突变对肺天然免疫功能的独立影响。目标2将定义渗透性T细胞的作用 在VM ILD的发展过程中的细胞，而AIM 3将定义EC中的VM驱动的信号事件以及 针对ILD的刺激靶向疗法。迫切需要为患者找到更好的治疗方法。 自身免疫性和自身炎症性肺疾病，本申请中提出的研究应该 提供关键的见解，使我们能够设计最好的治疗方法。此外，这些研究还将提供 有机会更广泛地研究刺痛对基质细胞类型的影响，这是一个新兴领域 最近研究表明，内皮细胞中的刺痛活性与严重的 COVID19.

Cyclic GMP-AMP synthase (cGAS) detects foreign DNA during infection or self-DNA leading to autoinflammatory diseases such as Aicardi-Goutieres syndrome. cGAS signals via STING, a receptor for cyclic GMP-AMP generated by cGAS. A series of gain-of-function mutations resulting in constitutive activation of STING have been associated with a debilitating autoinflammatory disease called STING-Associated- Vasculopathy with onset in Infancy (SAVI). SAVI patients suffer from severe vasculitic lesions and interstitial lung disease (ILD) and frequently succumb to respiratory failure. Like the lung conditions associated with other autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, very little is known about the mechanisms that promote inflammation in these patients. To gain insights into the mechanisms of STING driven inflammation in the lung, we have developed a murine model for the most common SAVI mutation, STINGV154M (VM), and found that mice heterozygous for this mutation develop immune abnormalities and lung disease. Lung endothelial cells are among the highest STING-expressing cells in the lung and based on our preliminary data we believe that auto-inflammation in the VM lung results from the direct effects of the SAVI mutation on “initiator” radioresistant cells (endothelial cells, and/or fibroblasts) resulting in stromal cell activation, differentiation, chemokine production and expansion. Lymphocytes (VM or WT) are then recruited to the lung. The recruited effector T cells further promote the pathogenic activity of both radioresistant cells and myeloid cells, leading to chronic inflammation; IFN plays a key role in this process. How the VM SAVI allele mediate disease pathogenesis in stromal cells remains unknown. We will focus on STING activation in endothelial cells and how these events lead to lymphocyte recruitment, activation and pathology. Aim 1 will determine the lymphocyte- independent effect of SAVI mutations on lung innate immune function. Aim 2 will define the role of infiltrating T cells in the development of VM ILD while Aim 3 will define VM-driven signaling events in ECs and the impact of STING-targeted therapeutics on ILD. There is an urgent need to identify better therapies for patients afflicted with autoimmune and autoinflammatory lung disorders and the studies proposed in this application should provide critical insights that will enable us to design the best therapies. Further, these studies will also provide an opportunity to study the impact of STING activation on stromal cell types more generally, an emerging area of research as STING activity in endothelial cells has recently been linked to the development of severe COVID19.