No abstract

The aim of this study was to evaluate the efficacy of human synovial membrane-derived MSCs (SM-MSCs) in murine collagen-induced arthritis (CIA). Male mice (age 7–9 weeks) were injected intra-articularly with SM-MSCs obtained from patients with osteoarthritis, on days 28, 32, and 38 after bovine type II collagen immunization. The efficacy of SM-MSCs in CIA was evaluated clinically and histologically. Cytokine profile analyses were performed by real-time polymerase chain reaction and multiplex analyses. Splenic helper T (Th) cell and regulatory B cell subsets were analyzed by flow cytometry. Intra-articular SM-MSC injection ameliorated the clinical and histological severity of arthritis. Decrease in tumor necrosis factor-α, interferon-γ, and interleukin- (IL-) 17A and increase in IL-10 production were observed after SM-MSC treatment. Flow cytometry showed that Th1 and Th17 cells decreased, whereas Th2, regulatory T (Treg), and PD-1+CXCR5+FoxP3+ follicular Treg cells increased in the spleens of SM-MSC-treated mice. Regulatory B cell analysis showed that CD21hiCD23hi transitional 2 cells, CD23lowCD21hi marginal zone cells, and CD19+CD5+CD1d+IL-10+ regulatory B cells increased following SM-MSC treatment. Our results demonstrated that SM-MSCs injected in inflamed joints in CIA had a therapeutic effect and could prevent arthritis development and suppress immune responses via immunoregulatory cell expansion.

No abstract

Rheumatoid arthritis (RA) is one of the most frequently occurring autoimmne diseases, with symptoms including synovium hyperplasia, immune disorder, cartilage damage and bone resorption. It has previously been demonstrated that microRNA-34a (miR-34a) may participate in cell apoptosis, immune activation and bone metabolism, therefore the present study investigated the effects of miR-34a on RA. Collagen-induced arthritic (CIA) mice were employed as a murine model of experimental arthritis, and it was demonstrated that the level of miR-34a in the spleens, lymph nodes and synovium was increased in the CIA mice compared with normal DBA/1j mice. Administration of miR-34a antagomir, the chemically modified inhibitor, ameliorated CIA and delayed the onset of symptoms. Arthritis scores decreased and joint swelling was alleviated with the miR-34a antagomir treatment and the expression of inflammatory cytokines was decreased. miR-34a antagomir delivery significantly decreased the percentage of T cells present including T helper (Th) 1, Th2, Th17 and regulatory T cells. Furthermore miR-34a antagomir-treated CIA mice demonstrated decreased inflammatory-induced bone loss. Overall, it was observed that inhibition of miR-34a ameliorated murine arthritis, downregulated T cell percentage and cytokine expression, and suppressed bone loss. The experimental results suggest that inhibition of miR-34a may offer a novel alternative for the treatment of RA.

Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. In this study, we report that decreased microRNA (miR)-200a-3p causes IL-2 hypoproduction through zinc finger E-box binding homeobox (ZEB)1 and C-terminal binding protein 2 (CtBP2) in a lupus-prone mouse. First, we performed RNA sequencing to identify candidate microRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, whereas its putative targets, ZEB2 and CtBP2, were upregulated in CD4 T cells from MRL/lpr- mice compared with C57BL/6J mice. ZEB1 and ZEB2 comprise the ZEB family and suppress various genes, including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance, and insufficient IL-2 production upon stimulation has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p causes IL-2 deficit through the ZEB1-CtBP2 and/or ZEB2-CtBP2 complex in SLE CD4 T cells. Overexpression of miR-200a-3p induced IL-2 production by downregulating ZEB1, ZEB2, and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promotes IL-2 expression by reducing the binding of suppressive ZEB1-CtBP2 and ZEB2-CtBP2 complexes on negative regulatory element A in the IL-2 promoter in EL4 cells. Interestingly, the ZEB1-CtBP2 complex on negative regulatory element A was significantly upregulated after PMA/ionomycin stimulation in lupus CD4 T cells. Our studies have revealed a new epigenetic pathway in the control of IL-2 production in SLE whereby low levels of miR-200a-3p accumulate the binding of the ZEB1-CtBP2 complex to the IL-2 promoter and suppress IL-2 production.