MicroRNAs as Active Players in the Pathogenesis of Multiple Sclerosis

Chiara Fenoglio,Elio Scarpini,Elisa Ridolfi,Daniela Galimberti

doi:10.3390/ijms131013227

Abstract

MicroRNAs (miRNAs) are a recently discovered group of small noncoding RNAs that regulate gene expression post-transcriptionally. They are highly expressed in cells of the immune system, as well as in the central nervous system, and they are deregulated in various neurological disorders. Emerging evidence underlines an involvement of miRNAs in the pathogenesis of Multiple Sclerosis (MS). A number of miRNAs have been found to be dysregulated in blood cells from MS patients, in brain lesions, as well as in biological fluids such as serum and plasma. Despite miRNA altered expression likely showing a high tissue specificity, some profile similarities could be observed for certain miRNAs such as miR-326—such as upregulation in both active lesions and blood—though not for others such as miR-323, which demonstrated upregulation in whole blood, active brain lesions, and T-reg cells, but not in the serum of MS patients. In this review, the possible role of miRNAs in MS pathogenesis will be discussed according to all the available literature, with a particular emphasis on the possibility of considering extracellular miRNAs as a new source for both biomarker identification and therapeutic target discovery.

Highlights

MicroRNAs are a class of small noncoding RNAs which have recently been discovered to be regulatory modulators of gene expression post-transcriptionally, either by targeting mRNA degradation or by inhibition of protein translation [1]. miRNAs directly modulate the expression of regulatory proteins that are required for normal development and function of the immune system.miRNAs have been estimated to roughly target 33% of human genes, highlighting their importance in gene regulation. miRNAs are expressed as 21–23 nucleotide RNA molecules initially transcribed by RNA polymerase II and III as long primary miRNAs
It has been shown that an individual miRNA is able to control the expression of more than one target mRNA and that each mRNA may be regulated by multiple miRNAs
In this study Murugaiyan showed that miR-155 expression was increased in CD4+T cells in EAE and that miR-155−/− mice had a delayed course and less severe disease with less inflammation in the central nervous system (CNS)

Summary

Introduction

MicroRNAs (miRNAs) are a class of small noncoding RNAs which have recently been discovered to be regulatory modulators of gene expression post-transcriptionally, either by targeting mRNA degradation or by inhibition of protein translation [1]. miRNAs directly modulate the expression of regulatory proteins that are required for normal development and function of the immune system. Producing T-helper CD4+ cells (Th-17 cells), which are a subset of the effector helper T cells necessary for clearing foreign pathogens and are involved in the pathogenesis of chronic autoimmune diseases, including MS [12] They demonstrated that miR-326 was over-expressed in Th-17 cells of patients with RRMS and promoted Th-17 differentiation, inhibiting Ets-1, a negative regulator of. Among the 723 human miRNAs tested, they found miR-106, miR-25, miR-19a and miR-19b significantly upregulated in Treg cells of MS patients versus controls These miRNAs modulate the TGF-β signaling pathway, silencing the cell cycle inhibitor CDKN1A (p21) and the pro-apoptotic geneBCL2L11 (BIM) [18]. Guerau-de-Arellano et al [20] demonstrated that the dysregulated miRNAs could suppress the Th2 pathway through repression of BMI1 and IL-4 and their overexpression may mean a predisposition to the development of a Th1 response and autoimmunity in MS patients [20]

Blood and Brain Lesions miRNA Profile

Extracellular miRNA Profile

MiRNA Therapeutic Potential

Treatment Effects on miRNA Profile

Findings

Conclusions