Dendritic Cells from Rheumatoid Arthritis Patient Peripheral Blood Induce Th17 Cell Differentiation via miR‐363/Integrin αv/TGF‐β Axis

Abstract

Dendritic cells (DCs) are critical regulators of immune responses. This study was to observe the effect of DCs from peripheral blood on the differentiation of Th17 in patients with rheumatoid arthritis (RA). Peripheral blood samples were collected from 30 patients with RA and 20 healthy controls, respectively. Flow cytometry results showed that in contrast to Treg cells, the proportion of Th17 cells in T cells and the Th17/Treg ratio were both increased in patients with RA. The RT-PCR results showed that Foxp3、ROR γt and miR-363 expression in PBMC of patients with RA were reduced, but the ITGAV expression was increased, which was negatively related to miR-363 expression. IL-17, TGF-β and IL-6 levels detected by ELISA were increased in peripheral blood serum of patients with RA. Moreover, we noted that the CD11C αν /CD11C DCs ratio was obvious increased in patients with RA and has positive correlation to the Th17/Treg ratio. In cocultured system, Th17 cell differentiation was significantly inhibited in the presence of ITGF-β suggesting that Th17 cell differentiation was controlled by active TGF-β (aTGF-β). After DCs transfecting with miR-363 mimics and cocultured with T cells, Th17 cell number, IL-17 level and ROR-γt expression were significantly reduced in the presence of latent TGF-β (ITGF-β). In addition, the integrin αv protein expression was both reduced in the presence of aTGF-β or ITGF-β. These data demonstrated that DCs induced Th17 cell differentiation through miR-363/Integrin αv/TGF-β pathway in patients with RA.

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

“…miR-223, a myeloid cell-specific miRNA and one of the most up-regulated miRNAs in patients with MS, can promote DC-induced activation of the pathogenic Th17 response. 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. This up-regulation promotes the development of autoreactive Th17 cells.…”

“…miR-363, 51 miR-142-3p 61 and miR-223 49 were dysregulated in DCs and could promote Th17 cell differentiation during the pathogenesis of autoimmune diseases. miR-363, 51 miR-142-3p 61 and miR-223 49 were dysregulated in DCs and could promote Th17 cell differentiation during the pathogenesis of autoimmune diseases.…”

“…50 The decreased expression of miR-363 in DCs from patients with RA leads to increased levels of IL-6, IL-17 and TGF-b in the serum. 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.…”

“…The miRNAs could modulate the balance of Th17/Treg in a cell non-autonomous way, that is, through targeting factors important for Th17 and Treg cell development in non-T cells. miR-363, 51 miR-142-3p 61 and miR-223 49 were dysregulated in DCs and could promote Th17 cell differentiation during the pathogenesis of autoimmune diseases. miR-363 suppresses the expression of integrin av, which is an important positive regulator of TGF-b activation.…”

Dysregulated ICOS+ proinflammatory and suppressive regulatory T cells�in patients with rheumatoid arthritis

“…The increase in ICOS + Tregs was larger in patients with iRA compared with those in patients with aRA, and the frequencies of ICOS + Tregs in patients with RA were negatively correlated with DAS28 scores. It was reported that IL-17, TGF-β and IL-6 levels detected by ELISA were increased in peripheral blood serum of patients with RA (30). Although the serum or plasma cytokines may reflect the status of disease in a patient, since several types of cells can secrete the total peripheral suppressive cytokines, the current study focused only on the cytokines produced current study suggests that an abnormal number of ICOS + Tregs and abnormal ICOS + Treg functions may contribute to the pathogenesis of RA.…”