The pathogenic role of miR-92a in the regulation of T helper cell responses in EAE and MS

miR-92a 在 EAE 和 MS 辅助 T 细胞反应调节中的致病作用

• 批准号: 10115610
• 负责人: Murugaiyan Gopal
• 金额: $ 55.78万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10115610
• 关键词: Animal Model; Anti-Inflammatory Agents; Attenuated; Biological Markers; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell physiology; Cells; Chronic; Clinical; Data; Development; Disease; Equilibrium; Experimental Autoimmune Encephalomyelitis; FOXO1A gene; Frequencies; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Mediating; MicroRNAs; Modeling; Molecular; Multiple Sclerosis; Mus; Neuraxis; Neurologic Symptoms; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pharmacology; Phenotype; Production; Regulation; Regulatory T-Lymphocyte; Relapse; Role; Severity of illness; T-Cell Development; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Treatment Efficacy; Untranslated RNA; attenuation; autoreactive T cell; cerebral atrophy; clinically relevant; immune function; in vivo; inhibitor/antagonist; interest; interleukin-23; multiple sclerosis patient; neuroinflammation; novel therapeutics; programs; response; therapeutic evaluation

Project Summary/Abstract MicroRNAs are critical gene expression regulators implicated in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, specific miRNA pathways that directly connect clinical activity with pathogenic and regulatory immune mechanisms in EAE and MS remains unclear. Recently, we identified a clinically relevant miRNA, miR-92a, whose expression is highly increased in MS patients and strongly associated with clinical disease activity and pathological immune mechanisms in EAE and MS. Specifically, our data suggest miR-92a promotes CNS inflammation by inhibiting Tregs and promoting Th17 and Th1 effector functions. MiR-92a levels are increased in EAE, and that miR-92a loss strikingly attenuates EAE. This attenuation is associated with increased Treg and decreased Th17 frequency, as well as decreased Th1/Th17 pathogenic effector molecules, notably GM-CSF. Mechanistically, miR-92a appears to inhibit Treg differentiation, stability, and suppressive function by directly targeting Foxo1. MiR-92a also promotes Th17 development by modulating Foxo1. In non-pathogenic Th17 cells, miR-92a inhibition of Foxo1 relieves RORgt from Foxo1-mediated inhibition, which in turn upregulates the Th17 transcriptional program. In pathogenic Th17 cells, miR-92a targeting of Foxo1 relieves IL-23R and IL-1R from Foxo1-mediated inhibition. This then enhances responsiveness to IL-23 and IL-1b, as well as GM-CSF production. In Th1 cells, miR-92a is dispensable for initial differentiation, but also promotes GM-CSF by targeting the Foxo1. Accordingly, T cell-specific deletion of miR-92a is sufficient to attenuate EAE, and miR- 92a inhibitor therapeutic effectively ameliorates EAE. Analogous to mice, miR-92a inhibits Tregs, while promoting Th17 development, in humans. Most importantly, miR-92a is increased in MS patient sera, which correlates with disease across multiple clinical parameters, including neurological symptoms and brain atrophy. We also show an increase in miR-92a in MS CD4+ T cells, which is associated with altered Treg/Th17 markers in MS. These findings suggest the pathogenic miR-92a-mediated pathways that mediate EAE may also modulate MS pathogenesis. Therefore, we will test our hypothesis that miR-92a promotes neuroinflammation in EAE and MS by two interlinked mechanisms: 1) inhibiting the development and function of Tregs; and 2) promoting pathogenic Th17/Th1 effector functions. In Aim 1, we will investigate the molecular mechanisms by which miR-92a control the balance of regulatory and inflammatory T cells in EAE and test the therapeutic efficacy of silencing miR-92a in clinically relevant EAE models. In Aim 2, we will investigate in humans the molecular mechanisms by which miR-92a controls the development of regulatory and inflammatory T cells and also study miR-92a as a biomarker, and miR-92a function, in MS and MS patient T cells. MiR-92a is of unique significance because it constitutes a single target modulating multiple T cell pathways in EAE/MS. Our findings will help navigate critical miR-92a-related mechanisms in MS that could underlie new therapeutic avenues.

项目概要/摘要 MicroRNA 是与多发性硬化症 (MS) 发病机制有关的关键基因表达调节因子 及其动物模型，实验性自身免疫性脑脊髓炎（EAE）。然而，特定的 miRNA 通路 将临床活动与 EAE 和 MS 的致病性和调节性免疫机制直接联系起来 仍不清楚。最近，我们鉴定了一种临床相关的 miRNA，miR-92a，其表达量高 MS 患者中升高，且与临床疾病活动性和病理免疫密切相关 EAE 和 MS 中的机制。具体来说，我们的数据表明 miR-92a 通过抑制 Tregs 并促进 Th17 和 Th1 效应器功能。 EAE 中 miR-92a 水平升高，并且 miR-92a 损失显着削弱了 EAE。这种减弱与 Treg 增加和 Th17 减少相关 频率，以及 Th1/Th17 致病效应分子，特别是 GM-CSF 的减少。从机械上来说， miR-92a 似乎通过直接靶向 Foxo1 来抑制 Treg 分化、稳定性和抑制功能。 MiR-92a 还通过调节 Foxo1 促进 Th17 发育。在非致病性 Th17 细胞中，miR-92a Foxo1 的抑制可缓解 Foxo1 介导的 RORgt 抑制，进而上调 Th17 转录程序。在致病性 Th17 细胞中，miR-92a 靶向 Foxo1 可减轻 IL-23R 和 IL-1R Foxo1 介导的抑制。这会增强对 IL-23 和 IL-1b 以及 GM-CSF 的反应性 生产。在 Th1 细胞中，miR-92a 对于初始分化是可有可无的，但也通过以下方式促进 GM-CSF： 针对 Foxo1。因此，T 细胞特异性删除 miR-92a 足以减弱 EAE，并且 miR-92a 92a 抑制剂治疗可有效改善 EAE。与小鼠类似，miR-92a 抑制 Tregs，而 促进人类 Th17 的发育。最重要的是，多发性硬化症患者血清中的 miR-92a 增加，这 与多种临床参数的疾病相关，包括神经系统症状和脑萎缩。 我们还发现 MS CD4+ T 细胞中 miR-92a 增加，这与 Treg/Th17 标记物的改变有关 在女士。这些发现表明，介导 EAE 的致病性 miR-92a 介导的途径也可能 调节 MS 发病机制。因此，我们将检验 miR-92a 促进神经炎症的假设 通过两个相互关联的机制在 EAE 和 MS 中发挥作用：1）抑制 Tregs 的发育和功能；和 2) 促进致病性 Th17/Th1 效应子功能。在目标 1 中，我们将通过以下方式研究分子机制： miR-92a控制EAE中调节性T细胞和炎症性T细胞的平衡并测试治疗效果 沉默 miR-92a 在临床相关 EAE 模型中的功效。在目标 2 中，我们将研究人类 miR-92a控制调节性T细胞和炎症性T细胞发育的分子机制 还研究 miR-92a 作为生物标志物，以及 miR-92a 在 MS 和 MS 患者 T 细胞中的功能。 MiR-92a 具有独特的 意义重大，因为它构成了 EAE/MS 中调节多个 T 细胞途径的单一靶点。我们的发现 将有助于探索 MS 中与 miR-92a 相关的关键机制，这可能成为新的治疗途径的基础。