Mechanisms of STING-driven autoinflammation

STING 驱动的自身炎症机制

• 批准号: 10681141
• 负责人: Katherine A. Fitzgerald
• 金额: $ 83.72万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681141
• 关键词: Alleles; Apoptosis; Area; Autoimmune; Autoimmune Diseases; Autophagocytosis; Binding; Cell Death; Cells; Chronic; Cyclic GMP; DNA; Data; Development; Disease; EIF-2alpha; Endothelial Cells; Endothelium; Event; Fibroblasts; Gene Expression; Genetic Transcription; Goals; Heterozygote; IFNAR1 gene; IRF3 gene; Immune; Infection; Inflammation; Inflammatory; Innate Immune Response; Interferon Type II; Interferons; Interstitial Lung Diseases; Lead; Lesion; Link; Lung; Lung diseases; Lymphocyte; Lymphocyte Depletion; Mediating; Mediator; Modality; Mus; Mutation; Myeloid Cells; PTPRC gene; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Play; Population; Process; Production; Rag1 Mouse; Research; Research Personnel; Respiratory Failure; Reticular Cell; Rheumatoid Arthritis; Role; Series; Signal Transduction; Stimulator of Interferon Genes; Stromal Cells; Systemic Scleroderma; T cell infiltration; T-Lymphocyte; T-cell receptor repertoire; TBK1 gene; Therapeutic; Vascular Diseases; autoinflammation; autoinflammatory; autoinflammatory diseases; cell type; chemokine; cytokine; design; effector T cell; gain of function mutation; in vivo; infancy; inhibitor; innate immune function; insight; interferon alpha receptor; mouse model; novel; pseudotoxoplasmosis syndrome; radioresistant; receptor; recruit; response; severe COVID-19; targeted treatment; tool; treatment strategy; type I interferon receptor

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.

环 GMP-AMP 合酶 (cGAS) 在感染过程中检测外源 DNA 或自身 DNA，从而导致 自身炎症性疾病，例如 Aicardi-Goutieres 综合征，通过 STING（一种循环受体）发出 cGAS 信号。 由 cGAS 产生的一系列功能获得性突变导致 GMP-AMP 的组成型激活。 STING 与一种名为 STING 相关的使人衰弱的自身炎症性疾病有关。 婴儿期发病的血管病 (SAVI) 患者患有严重的血管炎病变和间质性病变。 肺部疾病 (ILD) 并经常死于呼吸衰竭，就像与其他相关的肺部疾病一样。 类风湿性关节炎和系统性硬化症等自身免疫性疾病，人们对其知之甚少。 促进这些患者炎症的机制，以深入了解 STING 驱动的机制。 肺部炎症，我们针对最常见的 SAVI 突变 STINGV154M 开发了小鼠模型 (VM)，并发现这种突变杂合的小鼠会出现免疫异常和肺部疾病。 根据我们的初步数据，内皮细胞是肺部 STING 表达最高的细胞之一 我们认为VM肺部的自身炎症是由SAVI突变对“引发者”的直接影响造成的 抗辐射细胞（内皮细胞和/或成纤维细胞）导致基质细胞活化、分化， 然后淋巴细胞（VM 或 WT）被募集至肺部。 效应T细胞进一步促进放射抗性细胞和骨髓细胞的致病活性，导致 慢性炎症；IFN 在此过程中发挥关键作用 VM SAVI 等位基因如何介导疾病。 基质细胞的发病机制仍然未知，我们将重点关注内皮细胞中的 STING 激活以及如何激活。 这些事件导致淋巴细胞募集、激活和病理学，目标 1 将决定淋巴细胞。 SAVI 突变对肺先天免疫功能的独立影响将确定浸润性 T 的作用。 细胞在 VM ILD 的发展中，而目标 3 将定义 EC 中 VM 驱动的信号事件以及 ILD 的 STING 靶向治疗迫切需要为患者找到更好的治疗方法。 患有自身免疫性和自身炎症性肺部疾病，本申请中提出的研究应该 此外，这些研究还将提供重要的见解，使我们能够设计出最佳的疗法。 有机会更广泛地研究 STING 激活对基质细胞类型的影响，这是一个新兴领域 最近的研究表明，内皮细胞中的 STING 活性与严重疾病的发生有关 新冠肺炎。