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合成酶（cGAS）在感染过程中检测外源DNA或自身DNA导致