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: 10348726
• 负责人: Murugaiyan Gopal
• 金额: $ 28.67万
• 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/10348726
• 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; Treatment Efficacy; Untranslated RNA; attenuation; autoreactive T cell; cerebral atrophy; clinically relevant; immune function; in vivo; inhibitor; inhibitor therapy; 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.

项目总结/摘要 microRNA是多发性硬化（MS）发病机制中的关键基因表达调节因子 实验性自身免疫性脑脊髓炎（EAE）动物模型。然而，特定的miRNA途径 直接将临床活动与EAE和MS中的致病性和调节性免疫机制联系起来 仍不清楚最近，我们发现了一种临床相关的miRNA，miR-92 a，其表达高度依赖于细胞增殖。 MS患者中增加，并与临床疾病活动和病理免疫密切相关 具体地说，我们的数据表明miR-92 a通过抑制EAE和MS中的炎症机制促进CNS炎症。 T细胞活化并促进Th 17和Th 1效应子功能。miR-92 a水平在EAE中增加，并且miR-92 a 损失显著地减弱EAE。这种衰减与Treg增加和Th 17减少相关 频率，以及减少Th 1/Th 17致病性效应分子，特别是GM-CSF。机械地说， miR-92 a似乎通过直接靶向Foxo 1抑制Treg分化、稳定性和抑制功能。 MiR-92 a还通过调节Foxo 1促进Th 17发育。在非致病性Th 17细胞中，miR-92 a Foxo 1的抑制使RORgt从Foxo 1介导的抑制中释放，这反过来上调Th 17 转录程序在致病性Th 17细胞中，靶向Foxo 1的miR-92 a可减轻IL-23 R和IL-1 R， Foxo 1介导的抑制。然后，这增强了对IL-23和IL-1b以及GM-CSF的反应性。 生产在Th 1细胞中，miR-92 a被激活用于初始分化，但也通过以下方式促进GM-CSF： 目标是Foxo 1因此，miR-92 a的T细胞特异性缺失足以减弱EAE，并且miR-92 a的T细胞特异性缺失足以减弱EAE。 92 a抑制剂治疗有效地改善EAE。与小鼠类似，miR-92 a抑制TcR，而 促进Th 17在人类中的发育。最重要的是，miR-92 a在MS患者血清中增加， 与多种临床参数的疾病相关，包括神经症状和脑萎缩。 我们还显示MS CD 4 + T细胞中miR-92 a的增加，这与Treg/Th 17标志物的改变有关。 这些发现表明，介导EAE的致病性miR-92 a介导的途径也可能 调节MS发病机制。因此，我们将检验我们的假设，即miR-92 a促进神经炎症 在EAE和MS中通过两种相互关联的机制：1）抑制TAE的发展和功能;和2） 促进致病性Th 17/Th 1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： 其中miR-92 a控制EAE中调节性T细胞和炎性T细胞的平衡， 在临床相关EAE模型中沉默miR-92 a的功效。在目标2中，我们将在人类中研究 miR-92 a控制调节性和炎性T细胞发育的分子机制， 还研究了miR-92 a作为MS和MS患者T细胞中的生物标志物以及miR-92 a的功能。MiR-92 a具有独特的 因为它构成了调节EAE/MS中多种T细胞通路的单一靶点。 将有助于在MS中导航关键的miR-92 a相关机制，这可能是新的治疗途径的基础。