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.