miRNA-Dependent CD4+ T Cell Differentiation in the Pathogenesis of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is characterized by multifocal lesions, chronic inflammatory condition, and degenerative processes within the central nervous system (CNS) leading to demyelination. The most important cells involved in its pathogenesis are those which are CD4⁺, particularly proinflammatory Th1/Th17 and regulatory Treg. Signal cascades associated with CD4⁺ differentiation are regulated by microRNAs (miRNAs): short, single-stranded RNAs, responsible for negative regulation of gene expression at the posttranscriptional level. Several miRNAs have been consistently reported as showing dysregulated expression in MS, and their expression patterns may be elevated or decreased, depending on the function of specific miRNA in the immune system. Studies in MS patients indicate that, among others, miR-141, miR-200a, miR-155, miR-223, and miR-326 are upregulated, while miR-15b, miR-20b, miR-26a, and miR-30a are downregulated. Dysregulation of these miRNAs may contribute to the imbalance between pro- and anti-inflammatory processes, since their targets are associated with the regulation of Th1/Th17 and Treg cell differentiation. Highly expressed miRNAs can in turn suppress translation of key Th1/Th17 differentiation inhibitors. miRNA dysregulation may result from the impact of various factors at each stage of their biogenesis. Immature miRNA undergoes multistage transcriptional and posttranscriptional modifications; therefore, any protein involved in the processing of miRNAs can potentially lead to disturbances in their expression. Epigenetic modifications that have a direct impact on miRNA gene transcription may also play an important role.

Figure 1

Naive CD4⁺ cells are activated via antigen-presenting cell (APC) and differentiate into several subtypes, viz. Th1, Th2, Treg, or Th17, under the influence of specific cytokines. Differentiation of Th1 cells is stimulated by the presence of IL-12, which activates the signaling pathways associated with STAT proteins (STAT1 and STAT4) and T-bet transcription factor. Mature Th1 cells secrete proinflammatory cytokines: IL-2, IL-3, IFN-γ, and TNF-α. Th2 cells differentiate under the influence of IL-4 and STAT6, which activate GATA3 transcription factor and stimulate the production of cytokines, including IL-4, IL-5, IL-9, and IL-13. Treg cell differentiation is dependent on the presence of TGF-β, and the typical transcription factor expressed by Treg is FOXP3. TGF-β and IL-10 are also effector cytokines secreted by Treg cells. The presence of TGF-β and IL-6 stimulates the differentiation of Th17 cells through STAT3 signaling pathways, as well as transcription factors RORγt and RORα. In addition, Th17 differentiation can be induced by alternative pathways stimulated with IL-21 and IL-23 (activating STAT4). Major effector cytokines include IL-17, IL-17F, IL-21, and IL-22.

Figure 2

(a) Primary miRNA transcripts (pri-miRNAs) are processed in the nucleus via DROSHA and DGCR8 into pre-miRNAs. Pre-miRNAs are transported by XPO5 and RAN-GTP to the cytoplasm, where they are further transformed by Dicer and TARBP2 into mature molecules. (b) Methylation of the miRNA promoter sequence may have a direct effect on miRNA biogenesis. The MECP2 protein, by binding to methylated sequences, inhibits transcription and allows pri-miRNA processing, which increases the level of mature miRNAs. (c) Mature miRNAs can silence expression of target genes through two main mechanisms: repression of translation through the RISC complex and direct transcript degradation by AGO2.