Circulating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3+ regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. Here, we show that induction of human IFN-γ−IL-17A−Foxp3+CD4+ T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4+ T cells is reduced in patients with MS. Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway.

MicroRNA‐mediated regulation of T helper type 17/regulatory T‐cell balance in autoimmune disease

“…This up-regulation promotes the development of autoreactive Th17 cells. 53 Mechanisms through which dysregulated miRNAs modulate Th17/Treg balance During the development of autoimmune diseases, dysregulated miRNAs regulate Th17/Treg balance through targeting the positive or negative regulators of Th17 and/or Treg cell differentiation. 51 In addition, it has been reported that miR-663 in bone marrow-derived mesenchymal stem cells and miR-142-3p in monocyte-derived DCs suppress Treg cell development during the pathogenesis of SLE.…”

“…52 Recently, studies found that the expression of miRNA let-7i in circulating exosomes is markedly increased in patients with MS and this leads to the suppression of Treg cell development. 53 Mechanisms through which dysregulated miRNAs modulate Th17/Treg balance During the development of autoimmune diseases, dysregulated miRNAs regulate Th17/Treg balance through targeting the positive or negative regulators of Th17 and/or Treg cell differentiation. In this section, we will summarize different mechanisms through which dysregulated miRNAs modulate Th17/Treg balance during the development of autoimmune diseases (Fig.…”

“…52 The circulating exosomal miRNA, miR-let7i, which is markedly increased in patients with MS, suppresses the induction of Treg cells by targeting insulinlike growth factor 1 receptor and transforming growth factor b receptor. 53…”

Circulating exosomes cause loss of immunological balance in multiple sclerosis

“…Recently, we found that the expression profile of miRNAs in circulating exosomes was different in patients with multiple sclerosis (MS) compared with healthy controls (HC). 1 Among them, let-7i, miR-19b, miR-25, and miR-92a were increased in exosomes from patients with MS (MS-exosome). After human primary T cells were cultured with exosomes, the frequency of regulatory T cells (Treg cell), that were determined as IFN-c À IL-17A À Foxp3 + CD4 + T cells, was lower in the presence of MS-exosome than healthy control-exosome.…”

“…Recently, we found that the expression profile of miRNAs in circulating exosomes was different in patients with multiple sclerosis (MS) compared with healthy controls (HC) . Among them, let‐7i , miR‐19b , miR‐25 , and miR‐92a were increased in exosomes from patients with MS (MS‐exosome).…”