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

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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.