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

• 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
• 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

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.

项目总结/摘要 炎性和调节性T细胞之间的适当平衡对于维持免疫至关重要。 稳态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， EAE。虽然已知辅助性T细胞亚群的分化和致病性受特异性免疫调节， 转录因子和细胞因子，控制这些细胞平衡的microRNA的作用并不好 明白我们最近发现了微小RNA Mir-21在促进炎症反应中的重要作用， Th 17/Th 1细胞和抑制调节性Tr 35细胞。我们的初步数据显示， Mir-21通过这些细胞类型介导EAE中的组织炎症。具体来说，我们发现在Th 17细胞中，Mir- 21靶向Foxo 1，解除Foxo 1介导的IL-23 R和IL-1 R抑制，增强对IL-23 R和IL-1 R的反应性， 23和IL-1β的作用，并促进Th 17的致病性。Mir-21还促进GM-CSF在细胞内的表达。 通过靶向Foxo 1-IL-1 R轴分化Th 1细胞。Mir-21的缺失会干扰 Th 17/Th 1效应细胞因子GM-CSF在体内并赋予显著的EAE抗性。此外，我们的初步 数据显示，Mir-21可以通过阻止调节性Tr 35细胞的发展来促进自身免疫， 靶向IL-12 p35，细胞因子IL-35共享的亚基。与我们在老鼠身上的发现类似， Mir-21促进Th 17分化，同时抑制Tr 35细胞。有趣的是， 发现MS患者T细胞中Mir-21和其他Th 1/Th 17细胞因子的表达增加，IFN-β，a MS的一线治疗抑制T细胞中的Mir-21。最重要的是，我们发现来自IFN-β的CD 4 + T细胞 应答者表达较低水平的Mir-21，而无应答者的Mir-21水平与 未经治疗的患者然而，Mir-21在EAE中调节Th 17/Th 1和Tr 35细胞的确切作用， 人类，特别是MS患者，是未知的。在本提案中，我们将研究Mir-21如何调节 EAE和MS中炎症和抗炎T细胞的平衡。在目的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Th 17/Th 1致病功能和抑制Th 17/Th 1免疫功能的分子机制 调节Tr 35细胞。在目标2中，我们将从分子上定义Mir-21介导 促进Th 17细胞和抑制调节性Tr 35细胞，并调节其他T辅助细胞亚群， 人类鉴于我们在人类T辅助细胞和MS患者中的初步数据与鼠细胞类似， 和EAE小鼠，可能相同的关键致病性Mir-21介导的调节EAE的途径可能 也参与了MS的发病机制。因此，在目标3中，我们将研究Mir-21通路是否 影响MS患者炎症性Th 17/Th 1和调节性T细胞的平衡， 在治疗后会发生改变。更好地了解这些途径将有 对于探索MS的免疫机制以及它们如何与治疗功效相关具有重要意义。