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

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $286,665

## Abstract

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 i...

## Key facts

- **NIH application ID:** 10348726
- **Project number:** 5R01AI151953-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Murugaiyan Gopal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $286,665
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348726

## Citation

> US National Institutes of Health, RePORTER application 10348726, The pathogenic role of miR-92a in the regulation of T helper cell responses in EAE and MS (5R01AI151953-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10348726. Licensed CC0.

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