Role of IL-7R in CNS autoimmunity

IL-7R 在中枢神经系统自身免疫中的作用

• 批准号: 10308115
• 负责人: A.M. Rostami
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308115
• 关键词: Ablation; Affect; Agonist; Animal Model; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell Differentiation process; Cell physiology; Cells; Chronic; Complex; Data; Dendritic Cells; Development; Endothelin A Receptor; Endothelin-1; Etiology; Experimental Animal Model; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Fumarates; Genes; Genetic; Genetic Polymorphism; Granulocyte-Macrophage Colony-Stimulating Factor; Human; IL7 gene; IL7R gene; Immune Response Genes; Immune response; Immunize; Immunology; In Vitro; Inflammation; Inflammatory; Interleukin 2 Receptor Gamma; Interleukin 7 Receptor; Interleukin-9; Knockout Mice; Leukocytes; Literature; Mediating; Modeling; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Mus; Myelin; Pathogenesis; Pathogenicity; Pathway interactions; Play; Population; Predisposition; Production; Proteomics; Regulatory T-Lymphocyte; Relapse; Reporting; Resistance; Risk; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; analog; antagonist; base; central nervous system demyelinating disorder; conditional knockout; cytokine; experimental study; genetic approach; genetic risk factor; genome wide association study; in vivo; inducible gene expression; multiple sclerosis patient; multiple sclerosis treatment; neuroinflammation; next generation sequencing; novel strategies; polypeptide; receptor; receptor expression; single-cell RNA sequencing; therapeutic evaluation; transcriptomics; treatment effect

Summary: Role of IL-7R in CNS Autoimmunity IL-7 is an essential cytokine for the development of T and B cells and plays an important role in inflammation by stimulating Th1, Th17 cells and GM-CSF production. The IL-7 receptor (IL-7R) complex consists of IL-7R alpha-chain (IL-7Rα) and common γ-chain (γc) and polymorphisms in the IL-7Rα gene are associated with an increased risk for the development of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Although these observations suggest that signaling through IL-7R has a pathogenic role in CNS autoimmunity, its underlying mechanisms are unclear. In this regard, we have made the following preliminary observations: 1) Dendritic cells (DCs) express IL-7Rα in homeostatic conditions and during experimental autoimmune encephalomyelitis (EAE), an animal model of MS; 2) conditional knockout (cKO) mice lacking the IL-7Rα gene in DCs are protected from EAE; 3) IL-7Rα cKO EAE mice have a significant increase in IL-9+Foxp3+ regulatory T (Treg) cells; 4) IL-7Rα cKO DCs produce the vasoactive polypeptide Endothelin-1 (Edn-1); 5) DC-derived Edn-1 induces IL-9 production by T cells; and 6) Ab-mediated depletion of Treg cells or IL-9 restores EAE susceptibility in IL-7Rα cKO mice. Together, these and other observations form the bases of our hypothesis that IL-7Rα in DCs enhances EAE severity by suppressing the development of Edn-1- induced IL-9+ Treg cells. We will test this hypothesis in three Specific aims: 1) To dissect the mechanisms by which IL-7Rα downregulates Edn-1 production by DCs and promotes EAE. We will study the mechanisms by which IL-7Rα suppresses Edn-1 in mouse and human DCs, and the role of DC- derived Edn-1 on neuroinflammation by genetic ablation and inducible expression. 2) To investigate the signaling pathways by which Edn-1 induces IL-9+Foxp3+ Treg cells. We will investigate the mechanisms of IL-9 induction in Foxp3+ Treg cells by ETBR signaling by genetic approaches in vivo and in vitro, and study the effect of dimethyl fumarate, a common therapy for MS, on the expression profile of IL-7Rα+DCs, IL-9+Foxp3+ Treg cells and Edn-1 and its receptors in MS patients. 3) To test the therapeutic effect of Edn-1 and its analogues in EAE. This will be tested in myelin-reactive T cells, and multiple EAE models, including relapsing-remitting and chronic progressive EAE. Overall impact: Experiments in this study focusing on IL-7Rα, a genetic risk factor for MS, will enhance our understanding of the pathways and cellular interactions that promote CNS autoimmunity as well as investigate novel approaches to treat MS.

IL-7R在中枢神经系统自身免疫中的作用 IL-7是T、B细胞发育所必需的细胞因子，在T、B细胞发育中发挥重要作用。 通过刺激Th1、Th17细胞和GM-CSF产生炎症。IL-7受体(IL-7R)复合体 由IL-7Rα链(IL-7Rα)和公共γ链(γc)组成，以及IL-7Rα基因的多态性 与患多发性硬化症(MS)的风险增加有关，多发性硬化症是一种炎症性疾病 中枢神经系统(CNS)脱髓鞘疾病。尽管这些观察表明 通过IL-7R的信号在中枢神经系统自身免疫中起致病作用，其潜在机制是 不清楚。在这方面，我们做了以下初步观察：1)树突状细胞(DC) IL-7Rα在动态平衡和实验性自身免疫性脑脊髓炎中的表达 (2)树突状细胞中缺乏IL-7Rα基因的条件性基因敲除小鼠 IL-7RαCKO EAE小鼠IL-9+Foxp3+调节性T细胞显著增加 (TREG)细胞；4)IL-7RαCKO DC产生血管活性多肽内毒素-1(EDN-1)；5)DC来源的 EDN-1诱导T细胞产生IL-9；6)抗体介导的Treg细胞或IL-9耗竭恢复EAE IL-7RαCko小鼠的易感性。综合起来，这些和其他观察结果构成了我们 假设DC中的IL-7Rα通过抑制EDN-1的发展而增强EAE的严重性 诱导IL-9+Treg细胞。我们将在三个具体目标上检验这一假设：1)剖析 IL-7Rα下调DC产生EDN-1并促进EAE的机制。我们会研究 IL-7Rα抑制小鼠和人树突状细胞中EDN-1的机制及DC-1的作用 通过基因消融和诱导表达衍生的EDN-1对神经炎症的作用。2)调查 EDN-1诱导IL-9+Foxp3+Treg细胞的信号通路我们将研究其机制。 体内和体外ETBR信号通过遗传途径诱导Foxp3+Treg细胞产生IL-9，以及 富马酸二甲酯对多发性硬化患者外周血中IL-7Rα+DC表达的影响 多发性硬化患者IL-9+Foxp3+Treg细胞和EDN-1及其受体的变化3)测试治疗效果。 EAE中的EDN-1及其类似物。这将在髓鞘反应性T细胞和多种EAE模型中进行测试， 包括复发缓解型和慢性进展型EAE。 总体影响：这项研究的实验重点是IL-7Rα，一种多发性硬化症的遗传风险因素，将 增强我们对促进中枢神经系统自身免疫的途径和细胞相互作用的了解 并研究治疗多发性硬化症的新方法。