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: 10590651
• 负责人: Murugaiyan Gopal
• 金额: $ 42.22万
• 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/10590651
• 关键词: Animal Model; Anti-Inflammatory Agents; Attenuated; Biological Markers; CD4 Positive T Lymphocytes; CNS autoimmunity; Cell physiology; Cells; Central Nervous System; Chronic; Clinical; Data; Development; Disease; Disease remission; Equilibrium; Experimental Autoimmune Encephalomyelitis; FOXO1A gene; Frequencies; Functional disorder; Gene Expression; Genetic Transcription; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Human; IL1R1 gene; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Mediating; MicroRNAs; Modeling; Molecular; Multiple Sclerosis; Mus; Neurologic Symptoms; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phenotype; Production; Regulation; Regulatory T-Lymphocyte; Relapse; Role; Severity of illness; T cell differentiation; T-Cell Development; T-Lymphocyte; Testing; Th1 Cells; Treatment Efficacy; Untranslated RNA; attenuation; autoreactive T cell; cerebral atrophy; clinically relevant; immune function; immunoregulation; in vivo; inhibitor; inhibitor therapy; interest; interleukin-23; multiple sclerosis patient; neuroinflammation; novel therapeutics; pharmacologic; programs; response; therapeutic evaluation; therapeutically effective

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.

项目摘要/摘要 microRNA是与多发性硬化症（MS）发病机理有关的关键基因表达调节剂 及其动物模型，实验性自身免疫性脑脊髓炎（EAE）。但是，特定的miRNA途径 直接将临床活性与EAE和MS中的致病性和调节性免疫机制联系起来 仍然不清楚。最近，我们确定了临床上相关的miRNA miR-92a，其表达高度高 MS患者增加，与临床疾病活性和病理免疫密切相关 EAE和MS的机制。具体而言，我们的数据表明miR-92a通过抑制促进CNS炎症 Tregs并促进Th17和Th1效应子功能。 MiR-92a水平在EAE中升高，而miR-92a 损失极大地减弱了伊。这种衰减与Treg增加并减少Th17有关 频率以及降低TH1/TH17致病效应子分子，尤其是GM-CSF。机械上， miR-92a似乎通过直接靶向FOXO1抑制了Treg分化，稳定性和抑制功能。 miR-92a还通过调节FOXO1来促进TH17的开发。在非致病Th17细胞中，miR-92a FOXO1的抑制作用可以从FOXO1介导的抑制中缓解RORGT，这反过来又上调了TH17 转录程序。在致病性Th17细胞中，miR-92a FOXO1的靶向靶向IL-23R和IL-1R从 FOXO1介导的抑制作用。然后，这提高了对IL-23和IL-1B的响应能力以及GM-CSF 生产。在Th1细胞中，miR-92a对于初始分化是可分配的，但也可以通过 针对FOXO1。因此，miR-92a的T特异性缺失足以减弱EAE，而mir- 92A抑制剂治疗有效地改善了EAE。类似于小鼠，miR-92a抑制treg，而 在人类中促进Th17的发展。最重要的是，在MS患者血清中，miR-92a增加了，这 与多个临床参数的疾病相关，包括神经系统症状和脑萎缩。 我们还显示了MS CD4+ T细胞中miR-92a的增加，这与Treg/Th17标记的改变有关 在MS中。这些发现表明致病性miR-92a介导的途径也可能介导EAE 调节MS发病机理。因此，我们将测试miR-92a促进神经炎症的假设 在EAE和MS中通过两个相互联系的机制：1）抑制Treg的发展和功能；和2） 促进致病性TH17/TH1效应子功能。在AIM 1中，我们将通过 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 沉默miR-92a在临床相关的EAE模型中的功效。在AIM 2中，我们将在人类中调查 miR-92a控制调节性和炎症性T细胞以及 还将miR-92a作为生物标志物和MS患者T细胞中的miR-92a功能研究。 mir-92a是独特的 意义是因为它构成了单个目标调节EAE/MS中多个T细胞途径。我们的发现 将有助于在MS中驾驶与新的治疗途径的关键MIR-92A相关机制。