Abstract
Th17 cells are involved in rheumatoid arthritis (RA) pathogenesis. Our previous studies have revealed that transcription factor Yin Yang 1 (YY1) plays an important role in the pathogenic mechanisms of RA. However, whether YY1 has any role in Th17 cell pathogenicity and what molecular regulatory mechanism is involved remain poorly understood. Here, we found the proportion of pathogenic Th17 (pTh17) cells was significantly higher in RA than in control individuals and showed a potential relationship with YY1 expression. In addition, we also observed YY1 expression was increased in pTh17, and the pTh17 differentiation was hampered by YY1 knockdown. Consistently, knockdown of YY1 decreased the proportion of pTh17 cells and attenuated joint inflammation in collagen-induced arthritis mice. Mechanistically, YY1 could regulate the pathogenicity of Th17 cells through binding to the promoter region of transcription factor T-bet and interacting with T-bet protein. This function of YY1 for promoting pTh17 differentiation was specific to Th17 cells and not to Th1 cells. Moreover, we found miR-124-3p negatively correlated with YY1 in RA patients, and it could bind to 3′-UTR regions of YY1 to inhibit the posttranscriptional translation of YY1. Altogether, these findings indicate YY1 regulation by miR-124-3p could specifically promote Th17 cell pathogenicity in part through interaction with T-bet, and these findings present promising therapeutic targets in RA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by swollen joints and synovial inflammation as well as cartilage and bone erosion [1]
The results showed that the proportions of CD4+IL-17A+IFN-γ+ cells and CD4+IL-17A+GM-CSF+ cells were elevated in peripheral blood mononuclear cells (PBMCs) of patients with RA compared with patients with osteoarthritis (OA) and healthy donors (HDs) (Figure 1, A and B)
We found that Yin Yang 1 (YY1) mRNA expression was upregulated in purified CD4+ cells of patients with RA compared with HD (Figure 1F), and correlation analysis revealed there was still a positive correlation between YY1 and IL-17A (Figure 1G) yet no significant correlation between YY1 and IL-22 (Figure 1H) in purified CD4+ cells from patients with RA
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by swollen joints and synovial inflammation as well as cartilage and bone erosion [1]. The underlying pathophysiological mechanisms of RA are still largely unknown as it involves a complex interaction between genes and environment [2], increasing data demonstrate that the infiltration of inflammatory cells is one of the main etiological factors of RA. Th17 cells are a subset of CD4+ T cells and associated with the pathogenesis of various autoimmune disorders. Emerging evidence indicates that Th17 cells are heterogeneous and able to differentiate into diverse subsets with different phenotypes according to their pathogenicity. Th17 cells induced by TGF-β1/ IL-6 (known as nonpathogenic Th17, non-pTh17) benefit the homeostasis of tissues in certain conditions while those induced by IL-1β/IL-6/IL-23 (known as pathogenic Th17, pTh17) promote the tissue inflammation and pathogenesis of RA [5,6,7,8]. Pathogenic Th17 can be distinguished from nonpathogenic Th17 based on the different molecular programs. The precise mechanism of the generation and regulation of pTh17 is still largely unknown
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