Introduction
Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by chronic inflammatory cell infiltration and pannus formation in synovial tissues that lead to the destruction of articular cartilage and bone[1,2]. The inflamed synovium is hallmarked by inflammatory cells infiltration involving innate immune cells and adaptive cells (B cells and T cells)[3]. Although the pathogenesis of RA remains obscure, it has been accepted that the abnormal activation of CD4+T helper (Th) cells can cause the initiation and progression of RA[4]. Plasticity of CD4+T cells, the ability to differentiate into specific subsets, is essential for maintaining immune homeostasis[5]. In the stimulation of immunoregulatory cytokines such as TGF-β and IL-2, naïve CD4+ T cells could differentiate into Treg cells, which have a vital role in immune tolerance by suppressing pathogenic T cell responses[6]. Recently, quantitative and functional defects of Treg cells have been determined in the peripheral blood (PB) and synovial fluid of RA patients[7,8]. Treg cells are well-characterized for their specific expression of and Foxp3, and can secrete anti-inflammatory cytokines such as TGF-β, IL-10, IL-35, which inhibit effector T cells differentiation and function[9,10]. The modulation on Treg cells differentiation could be helpful for the treatment of RA.
The role of Treg cells in RA is clear, but the exact mechanisms were still being worked out. MicroRNAs (miRNAs), considered as a class of meticulous regulator for targeting messenger RNA (mRNA). They impact the expression of functional crosstalk genes and participate in the etiologic of inflammatory diseases[11,12]. Mounting evidence suggests that miRNAs are irreplaceable regulators on part of Treg cell differentiation and/or function. For instance, miR-146a and miR-155 was downregulated in Treg cells of RA patients, and correlated with joint inflammation[13]. MiR-342 was confirmed to control Treg regulatory functions via targeting the mTORC2 component, Rictor[14]. Simultaneously, miR-142-3p was reported to target Tet2 and result in impaired Treg stability in islet autoimmunity[15]. MiR-34a could attenuate Foxp3 gene expression via targeting their 3’ untranslated regions (3’ UTR) in collagen induced arthritis (CIA) mice[16]. However, whether other miRNAs participate in regulating Treg cell differentiation and/or function and how these miRNAs are regulated need further investigation.
Our previous studies have also found the abnormal expression of miR-143-3p in PB of RA patients by miRCURYTM LNA Array[17]. And in the present study, we demonstrated that miR-143-3p attained the highest negative correlation with RA disease activity, and it positively correlated with IL-10 in RA. We then designed the in vivo and in vitro experiments and verified the effect of miR-143-3p on Treg cell differentiation. Our data suggested that up-regulation of miR-143-3p markedly ameliorates CIA pathogenesis by inducing Treg cell differentiation. Overall, this study explored the role of miR-143-3p on Treg cell differentiation in RA pathogenies, which identified a promising new target for curing RA.