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: 9330530
• 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/9330530
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Autoimmunity; CD4 Positive T Lymphocytes; CNS autoimmunity; Cells; Clinical; Complex; Data; Defect; Development; Employee Strikes; Equilibrium; Experimental Autoimmune Encephalomyelitis; FOXO1A gene; FOXP3 gene; Functional disorder; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Hereditary Disease; 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; 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.

项目摘要/摘要 炎症和调节性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， 尽管已知T Helper子集的分化和致病性受到特定的调节 转录因子和细胞因子，控制这些细胞平衡的microRNA的作用不好 理解齿。我们最近发现了microRNA，miR-21在促进炎症中的重要作用 Th17/Th1细胞并抑制小鼠和人类的调节性TR35细胞。我们的初步数据表明 miR-21通过这些细胞类型介导EAE中的组织注射。具体而言，我们发现在Th17细胞中，mir- 21靶标FOXO1，从FOXO1介导的抑制中拯救IL-23R和IL-1R，提高了对IL-的响应能力 23和IL-1β，并促进Th17致病性。 miR-21还促进了GM-CSF的表达 通过靶向FOXO1-IL-1R轴来区分TH1细胞。 miR-21的丧失会干扰表达 Th17/Th1效应子细胞因子GM-CSF体内并承认引人注目的EAE耐药性。此外，我们的初步 数据表明，miR-21可以通过防止调节性TR35细胞的发展来促进自身免疫性 靶向IL-12p35，这是细胞因子IL-35共享的亚基。对我们在老鼠中发现的结果是相似的，我们发现 该miR-21在人类中促进了Th17分化，而抑制TR35细胞。有趣的是，我们也有 发现在MS患者中，MiR-21在T细胞和其他Th1/Th17细胞因子中的表达增加，而IFN-β，A，A MS的一线治疗可抑制T细胞中的miR-21。最重要的是，我们发现来自IFN-β的CD4+ T细胞 响应者表示miR-21的水平较低，而非反应者与 未经治疗的患者。但是，miR-21在EAE和 人类，特别是MS患者，尚不清楚。在此提案中，我们将调查miR-21如何调节 EAE和MS中炎症和抗炎T细胞的平衡。在AIM 1中，我们将调查 MiR-21促进Th17/Th1的致病功能并抑制的分子机制 EAE中的调节性TR35细胞。在AIM 2中，我们将分子定义miR-21培养基的机制 促进Th17细胞并抑制调节性TR35细胞，并调节其他T辅助子集 人类。鉴于我们在人类T辅助细胞和MS患者中的初步数据类似于鼠细胞 和EAE小鼠，可能会调节EAE的相同关键的致病miR-21介导的途径 也参与MS发病机理。因此，在AIM 3中，我们将研究miR-21途径是否 影响MS患者的炎症性TH17/TH1和调节性T细胞的平衡以及是否调节 通过这些途径，对治疗有所改变。更好地了解这些途径 对MS中的免疫力学导航及其与治疗效率的关系的重要意义。