cGAMP as an immunotransmitter of the interferon response to UV light

cGAMP 作为干扰素对紫外线反应的免疫递质

• 批准号: 10215860
• 负责人: Keith B. Elkon
• 金额: $ 42.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215860
• 关键词: Acute; Affect; Anions; Antigen-Antibody Complex; Autoimmune; Autoimmunity; Blood; Blood Cells; Bone Marrow; Cell Death; Cells; Characteristics; Chimera organism; Cleaved cell; Clinical; Connexins; DNA; DNA Damage; Dendritic Cells; Dinucleoside Phosphates; Disease; Dose; Environmental Risk Factor; Enzymes; Exposure to; Extracellular Fluid; Flare; Genetic; Genetic Predisposition to Disease; Goals; Immune; Immune response; In Vitro; Individual; Inflammation; Injury; Integral Membrane Protein; Interferon Type I; Interferons; Kidney; Knock-in; Lead; Lesion; Light; Lupus; Malignant Neoplasms; Manuscripts; Molecular; Mus; Nucleoproteins; Pathogenesis; Pathway interactions; Patients; Periodicity; Pharmacology; Plasma Cells; Population; Positioning Attribute; Production; Proteins; Radiation therapy; Reagent; Regulation; Reporting; Research; Role; SLC19A1 gene; Signal Transduction; Skin; Source; Stimulator of Interferon Genes; Surface; Systemic Lupus Erythematosus; T cell response; T-Cell Activation; Testing; Therapeutic; Tissues; UV Radiation Exposure; Ultraviolet Rays; Virus Diseases; Wild Type Mouse; autoinflammatory; base; cell motility; draining lymph node; extracellular; genetic approach; immune activation; immune function; keratinocyte; migration; mouse model; mutant; patient subsets; phosphoric diester hydrolase; plasma cell membrane glycoprotein PC-1; prevent; response; sensor; sunlight-induced; targeted treatment; therapy design; transmission process; ultraviolet

Project Summary The long-term goals of this project are to determine the role of the cGAS-STING pathway and the messenger cyclic dinucleotide cGAMP, as a local and systemic immunotransmitter of the IFN response following skin exposure to UVB light. In addition, we seek to determine the significance of these observations in a relevant mouse model of SLE. SLE patients characteristically have a type I interferon (IFN-I) signature in peripheral blood cells and this same signature is prominent in lesional and non-lesional skin. While it is generally assumed that systemic immune activation leads to dissemination of the IFN-I response to tissues, we observed that, following a single exposure to ultraviolet light (UVB), UVB induces an IFN signature not only in the skin but also in the blood and kidneys of wild type mice. Since we observed that IFN-I produced soon after UV exposure requires the DNA activated cytoplasmic sensor cGAS, we hypothesize that cGAMP, the cyclic dinucleotide synthetic product of cGAS, is itself an immunotransmitter that is responsible for spreading the IFN-I response locally and systemically. In this proposal, we explore how UVB stimulated cGAMP production leads to spreading of the IFN signature in the skin, examine the effects on local immune response in the draining lymph nodes, and look for cGAMP dependent tissue inflammation in both wild type and lupus-prone strains. To achieve these Aims, we take advantage of genetically modified mice that are deficient in cGAS or ENPP1 (ectonucleotide pyrophosphatase phosphodiesterase-1 that hydrolyzes cGAMP after export from cells) and utilize reagents that can be exploited to manipulate the cGAS-STING pathway. We specifically interrogate the cGAMP transporters: connexins, SLC19A1 and the Volume Regulated Anion Channel (VRAC) LRRC8, to determine which transporters control cGAMP spreading and under what conditions. The significance of these studies are that they will help define the genetic and molecular mechanisms responsible for UVB induction of IFN-I, define how the signal spreads and, possibly, indicate how lupus flares occur following exposure to UVB. In addition, the research focuses on an enzyme, ENPP1, that has not previously been studied in the context of autoimmunity and, if shown to be important, could be harnessed therapeutically to abort cGAMP spreading. These studies could reverse the paradigm that systemic IFN-I causes the skin IFN signature. Since we have detected cGAMP in blood of a subset of patients with systemic lupus erythematosus (SLE), the results of these studies will have strong translational significance.

项目总结

项目成果

Role of the cGAS-STING pathway in systemic and organ-specific diseases.

• DOI: 10.1038/s41581-022-00589-6
• 发表时间: 2022-09
• 期刊: Nature reviews. Nephrology