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NF-κB-driven miR-34a impairs Treg/Th17 balance via targeting Foxp3.
Xie M1, Wang J2, Gong W2, Xu H2, Pan X2, Chen Y2, Ru S2, Wang H2, Chen X2, Zhao Y3, Li J4, Yin Q5, Xia S2, Zhou X2, Liu X6, Shao Q7.
Author information
1Reproductive Sciences Institute, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, PR China; Department of Immunology, Nanjing Medical University, Nanjing, 211166, Jiangsu, PR China.2Reproductive Sciences Institute, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, PR China.3Bioinformatics Research Group, Key Laboratory of Intelligent Information Processing, Institute of Computing Technology, Chinese Academy of Sciences, Beijing, 100080, PR China.4Department of Rheumatology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, PR China.5Department of Clinical Laboratory, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, PR China.6Reproductive Sciences Institute, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, PR China. Electronic address: 1984lxia@163.com.7Reproductive Sciences Institute, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, PR China. Electronic address: shao_qx@ujs.edu.cn.
Abstract
The subset of regulatory T (Treg) cells, with its specific transcription Foxp3, is a unique cell type for the maintenance of immune homeostasis by controlling effector T (Teff) cell responses. Although it is common that a defect in Treg cells with Treg/Teff disorder causes autoimmune diseases; however, the precise mechanisms are not thoroughly revealed. Here, we report that miR-34a could attenuate human and murine Foxp3 gene expression via targeting their 3′ untranslated regions (3′ UTR). The human miR-34a, increased in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) patients, displayed a positive correlation with some serum markers of inflammation including rheumatoid factor (RF), anti-streptolysin antibody (ASO), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as well as Th17 signature gene RORγt, but inversely correlated with the mRNA expression levels of FOXP3. In addition, murine miR-34a levels were downregulated in TGF-β-induced Treg cells but upregulated in Th17 cells induced in vitro compared to activated CD4+ T cells. It has also been demonstrated that elevated miR-34a disrupting Treg/Th17 balance in vivo contributed to the progress of pathogenesis of collagen induced arthritis (CIA) mice. Furthermore, IL-6 and TNF-α were responsible for the upregulation of miR-34a and downregulation of Foxp3, which was reverted by the addition of NF-κB/p65 inhibitor BAY11-7082, thus indicating that NF-κB/p65 inhibited Foxp3 expression in an miR-34a-dependent manner. Finally, IL-6 or TNF-α-activated p65 could bind to the miR-34a promotor and enhance its activity, resulting in upregulation of its transcription. Taken together, we show that NF-κB activated by inflammatory cytokines, such as IL-6 and TNF-α, ameliorates Foxp3 levels via regulating miR-34a expression, which provides a new mechanistic and therapeutic insight into the ongoing of autoimmune diseases.