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.

总结：IL-7 R在CNS自身免疫中的作用 IL-7是T细胞和B细胞发育的必需细胞因子，并在T细胞和B细胞的发育中起重要作用。 通过刺激Th 1、Th 17细胞和GM-CSF的产生来刺激炎症。IL-7受体（IL-7 R）复合物 由IL-7 R α链（IL-7 R α）和共同γ链（γc）以及IL-7 R α基因多态性组成 与多发性硬化症（MS）的发展风险增加有关，多发性硬化症是一种炎症性疾病， 中枢神经系统（CNS）的脱髓鞘疾病。尽管这些观察表明， 通过IL-7 R的信号传导在CNS自身免疫中具有致病作用，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（DCs） 在稳态条件下和实验性自身免疫性脑脊髓炎期间表达IL-7 R α (EAE)，MS的动物模型; 2）在DC中缺乏IL-7 R α基因的条件性敲除（cKO）小鼠， 3）IL-7 R α cKO EAE小鼠的IL-9+ Foxp 3+调节性T细胞显著增加， （Treg）细胞; 4）IL-7 R α cKO DC产生血管活性多肽内皮素-1（Edn-1）; 5）DC衍生的 Edn-1诱导T细胞产生IL-9;和6）Ab介导的Treg细胞或IL-9的消耗恢复EAE IL-7 R α cKO小鼠的易感性。总之，这些和其他观察构成了我们的基础。 假设DC中的IL-7 R α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中检验这一假设：1）剖析 IL-7 R α下调DCs分泌Edn-1并促进EAE的机制。我们将研究 IL-7 R α抑制小鼠和人DC中Edn-1的机制，以及DC-1的作用。 通过基因消融和诱导表达衍生Edn-1对神经炎症的影响。2)探讨 Edn-1诱导IL-9+ Foxp 3 + Treg细胞的信号传导途径。我们将研究 通过体内和体外遗传方法通过ETBR信号传导在Foxp 3 + Treg细胞中诱导IL-9，和 研究MS常用治疗药物富马酸二甲酯对IL-7 R α+DCs表达谱的影响， MS患者中IL-9+ Foxp 3 + Treg细胞和Edn-1及其受体。3)为了测试 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行性EAE。 总体影响：本研究中的实验重点是IL-7 R α，MS的遗传风险因素， 增强我们对促进CNS自身免疫的途径和细胞相互作用的理解， 并研究治疗MS的新方法。