Differentiation of Pathogenic Th17 Cells Is Negatively Regulated by Let-7 MicroRNAs in a Mouse Model of Multiple Sclerosis.

Constance C Angelou,Rebecca Lawlor,Shelly R Peyton,Barbara A Osborne,Carey E Dougan,Jyothi Vijayaraghavan,Motoko Y Kimura,Elena L Pobezinskaya,Leonid A Pobezinsky,Vanja Lazarevic,Elizabeth Iverson,Lisa M Minter,Alexandria C Wells

doi:10.3389/fimmu.2019.03125

Abstract

Multiple sclerosis (MS) is a disabling demyelinating autoimmune disorder of the central nervous system (CNS) which is driven by IL-23- and IL-1β-induced autoreactive Th17 cells that traffic to the CNS and secrete proinflammatory cytokines. Th17 pathogenicity in MS has been correlated with the dysregulation of microRNA (miRNA) expression, and specific miRNAs have been shown to promote the pathogenic Th17 phenotype. In the present study, we demonstrate, using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), that let-7 miRNAs confer protection against EAE by negatively regulating the proliferation, differentiation and chemokine-mediated migration of pathogenic Th17 cells to the CNS. Specifically, we found that let-7 miRNAs may directly target the cytokine receptors Il1r1 and Il23r, as well as the chemokine receptors Ccr2 and Ccr5. Therefore, our results identify a novel regulatory role for let-7 miRNAs in pathogenic Th17 differentiation during EAE development, suggesting a promising therapeutic application for disease treatment.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects ∼2.5 million people worldwide, with a strong predominance in women [1]
We used EAE susceptibility as a readout of CD4+ T cell differentiation in doxycycline- or vehicle-treated let-7g transgene (Let-7Tg) and WT control mice immunized with the peptide antigen myelin oligodendrocyte glycoprotein, residues 35–55 (MOG35−55), in complete Freund’s adjuvant (CFA)
We found that, to CD8+ T cells [28], the expression of let-7 miRNAs in naïve CD4+ T cells is downregulated upon activation, which is essential for the clonal expansion, acquisition of pathogenic Th17 phenotype, and migration to the CNS

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects ∼2.5 million people worldwide, with a strong predominance in women [1]. The animal model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE), recapitulates the pathological and clinical symptoms of MS and has been extensively used to study this disorder [2]. In both MS and EAE, autoreactive CD4+ type-17 helper T (Th17) cells that are generated by exposure to IL-23 and IL-1β [3,4,5] migrate to the CNS and cross the blood-brain barrier by following gradients of chemokines secreted by CNS-resident innate lymphoid cells [6]. GM-CSF is a proinflammatory cytokine essential for disease induction as it promotes the activation, differentiation, and recruitment of monocytes and dendritic cells to the CNS, as. Inflammatory myeloid cells produce reactive oxygen species and cytokines that cause neuron demyelination and axonal damage, which leads to the disruption of neuronal signaling, eventually resulting in disabling physical symptoms, including progressive loss of motor function, which reflect the extent of neurodegeneration [1]

Methods

Results

Conclusion