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）在感染期间检测外源DNA或自身DNA，导致感染。 自身炎症性疾病，如Aicardi-Goutieres综合征。cGAS通过STING信号传导，STING是一种环 由cGAS产生的GMP-AMP。一系列的功能获得性突变导致了 STING与一种称为STING相关的自身炎症性疾病有关， 婴儿期发作的血管病变（SAVI）。SAVI患者患有严重的血管炎性病变和间质性病变。 肺疾病（ILD），并经常死于呼吸衰竭。就像与其他疾病相关的肺部疾病一样， 自身免疫性疾病，如类风湿性关节炎和系统性硬化症，很少有人知道， 促进这些患者炎症的机制。深入了解STING驱动的机制 我们建立了一个最常见的SAVI突变STINGV 154 M的小鼠模型， (VM)发现这种突变的杂合子小鼠会出现免疫异常和肺部疾病。肺 内皮细胞是肺中STING表达最高的细胞之一，根据我们的初步数据， 我们认为VM肺中的自身炎症是由SAVI突变对“起始物”的直接影响引起的， 放射抗性细胞（内皮细胞和/或成纤维细胞）导致基质细胞活化，分化， 趋化因子的产生和扩增。然后将淋巴细胞（VM或WT）募集到肺中。招募的 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 γ在此过程中起关键作用。VM SAVI等位基因如何介导疾病 间质细胞的发病机制仍不清楚。我们将专注于内皮细胞中的STING激活以及如何 这些事件导致淋巴细胞募集、活化和病理学。目标1将确定淋巴细胞- SAVI突变对肺先天免疫功能的独立影响。目标2将定义渗透T细胞的作用， 而目标3将定义EC中VM驱动的信号传导事件以及 STING靶向治疗ILD。目前迫切需要为受影响的患者确定更好的治疗方法 自身免疫性和自身炎性肺病，本申请中提出的研究应 提供关键的见解，使我们能够设计最好的疗法。此外，这些研究还将提供 有机会研究STING激活对基质细胞类型的影响，更普遍地说，这是一个新兴的领域。 最近，内皮细胞中的STING活性与严重的 COVID 19.