MICRORNA CONTROL OF INFLAMMATORY AND REGULATORY T CELLS IN CENTRAL NERVOUS SYSTEM AUTOIMMUNITY

中枢神经系统自身免疫炎症和调节 T 细胞的微 RNA 控制

基本信息

批准号：
9418583
负责人：
Murugaiyan Gopal
金额：
$ 43.94万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9418583
关键词：
Animal Model Anti-inflammatory Autoimmune Diseases Autoimmunity CD4 Positive T Lymphocytes CNS autoimmunity Cells Clinical Complex Data Defect Development Equilibrium Experimental Autoimmune Encephalomyelitis FOXO1A gene FOXP3 gene Functional disorder Genetic Diseases Granulocyte-Macrophage Colony-Stimulating Factor Helper-Inducer T-Lymphocyte Homeostasis Human Immune In Vitro Inflammation Inflammation Mediators Inflammatory Interferon-beta Interleukin-1 beta Interleukin-17 Link Mediating MicroRNAs Molecular Multiple Sclerosis Mus Neuraxis Pathogenesis Pathogenicity Pathway interactions Patients Regulation Regulatory T-Lymphocyte Resistance Role Serum T cell differentiation T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tissues Treatment Efficacy autoreactivity base cell type cytokine design experimental study improved in vivo insight interest interleukin-23 multiple sclerosis patient multiple sclerosis treatment novel novel therapeutic intervention prevent response transcription factor white matter

项目摘要

Project Summary/Abstract An appropriate balance between inflammatory and regulatory T cells is critical to maintaining immune homeostasis and preventing autoimmune diseases, including multiple sclerosis (MS) and its animal model, EAE. Although the differentiation and pathogenicity of T helper subsets is known to be regulated by specific transcription factors and cytokines, the role of microRNAs that control the balance of these cells is not well understood. We recently uncovered an important role for the microRNA, Mir-21 in promoting inflammatory Th17/Th1 cells and inhibiting regulatory Tr35 cells in both mice and humans. Our preliminary data suggest that Mir-21 mediates tissue inflammation in EAE via these cell types. Specifically, we found that in Th17 cells, Mir- 21 targets Foxo1, relieves IL-23R and IL-1R from Foxo1-mediated inhibition, enhances responsiveness to IL- 23 and IL-1β, and promotes Th17 pathogenicity. Mir-21 also promotes GM-CSF expression within differentiated Th1 cells by targeting the Foxo1-IL-1R axis. Loss of Mir-21 interferes with the expression of the Th17/Th1 effector cytokine GM-CSF in vivo and confers striking EAE resistance. In addition, our preliminary data show that Mir-21 may promote autoimmunity by preventing the development of regulatory Tr35 cells by targeting IL-12p35, a subunit shared by the cytokine IL-35. Analogous to our findings in mice, we have found that Mir-21 promotes Th17 differentiation, while inhibiting Tr35 cells, in humans. Interestingly, we have also found increased expression of Mir-21 in T cells and other Th1/Th17 cytokines in MS patients, and that IFN-β, a first-line therapy for MS, inhibits Mir-21 in T cells. Most importantly, we found that CD4+ T cells from IFN-β responders expressed lower levels of Mir-21, and that non-responders had indistinguishable levels from untreated patients. However, the exact role of Mir-21 in the regulation of Th17/Th1 and Tr35 cells in EAE and humans, specifically MS patients, is not known. In this proposal, we will investigate how Mir-21 regulates the balance of inflammatory and anti-inflammatory T cells in EAE and MS. In Aim 1, we will investigate the molecular mechanisms by which Mir-21 promotes the pathogenic functions of Th17/Th1 and inhibition of regulatory Tr35 cells in EAE. In Aim 2, we will molecularly define the mechanisms by which Mir-21 mediates promotion of Th17 cells and inhibition of regulatory Tr35 cells, and modulates other T helper subsets in humans. Given that our preliminary data in human T helper cells and MS patients is analogous to murine cells and EAE mice, it is possible that the same critical pathogenic Mir-21-mediated pathways modulating EAE may also be involved in the MS pathogenesis. Therefore, in Aim 3, we will investigate whether Mir-21 pathways influence the balance of inflammatory Th17/Th1 and regulatory T cells in MS patients and whether regulation by these pathways is altered in response to therapy. A better understanding of these pathways will have important implications for navigating immune mechanisms in MS and how they relate to therapeutic efficacy.

项目概要/摘要炎症性 T 细胞和调节性 T 细胞之间的适当平衡对于维持免疫系统至关重要体内平衡和预防自身免疫性疾病，包括多发性硬化症（MS）及其动物模型，尽管已知辅助 T 亚群的分化和致病性受特定调节。转录因子和细胞因子，控制这些细胞平衡的microRNA的作用还不是很好我们最近发现了 microRNA Mir-21 在促进炎症方面的重要作用。我们的初步数据表明，小鼠和人类的 Th17/Th1 细胞和抑制调节性 Tr35 细胞。 Mir-21 通过这些细胞类型介导 EAE 中的组织炎症，我们发现在 Th17 细胞中，Mir-21 介导 EAE 中的组织炎症。 21 靶向 Foxo1，解除 Foxo1 介导的 IL-23R 和 IL-1R 抑制，增强对 IL-23R 和 IL-1R 的反应 Mir-21 还促进 GM-CSF 表达。通过靶向 Foxo1-IL-1R 轴来分化 Th1 细胞 Mir-21 的丢失会干扰 Th1 细胞的表达。 Th17/Th1 效应细胞因子 GM-CSF 在体内并赋予显着的 EAE 抵抗力。数据显示 Mir-21 可能通过阻止调节性 Tr35 细胞的发育来促进自身免疫靶向 IL-12p35，细胞因子 IL-35 共有的一个亚基，与我们在小鼠中的发现类似，我们发现。 Mir-21 促进人类 Th17 细胞分化，同时抑制 Tr35 细胞。发现 MS 患者的 T 细胞和其他 Th1/Th17 细胞因子中 Mir-21 的表达增加，并且 IFN-β（一种 MS 的一线疗法，抑制 T 细胞中的 Mir-21 最重要的是，我们发现 CD4+ T 细胞来自 IFN-β。应答者的 Mir-21 水平较低，而无应答者的 Mir-21 水平与无应答者的水平无法区分。然而，Mir-21 在 EAE 和 Th17/Th1 和 Tr35 细胞调节中的确切作用。人类，特别是多发性硬化症患者，尚不清楚。在本提案中，我们将研究 Mir-21 如何调节。在目标 1 中，我们将研究 EAE 和 MS 中炎症和抗炎 T 细胞的平衡。 Mir-21促进Th17/Th1致病功能和抑制Th17/Th1致病功能的分子机制在目标 2 中，我们将从分子角度定义 Mir-21 介导的机制。促进 Th17 细胞和抑制调节性 Tr35 细胞，并调节其他 T 辅助细胞亚群鉴于我们在人类 T 辅助细胞和多发性硬化症患者中的初步数据与小鼠细胞类似。和 EAE 小鼠，调节 EAE 的相同关键致病性 Mir-21 介导的途径可能因此，在目标 3 中，我们将研究 Mir-21 通路是否参与。影响 MS 患者炎症 Th17/Th1 和调节性 T 细胞的平衡以及调节是否这些途径会因治疗而改变。对这些途径有更好的了解。对于探索多发性硬化症的免疫机制及其与治疗效果的关系具有重要意义。