NF-κB-driven miR-34a impairs Treg/Th17 balance via targeting Foxp3
NF-κB-driven miR-34a impairs Treg/Th17 balance via targeting Foxp3
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NF-κB 驱动的 miR-34a 通过靶向 Foxp3 损害 Treg/Th17 平衡。
DOI：
10.1016/j.jaut.2019.04.018
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发表时间：
2019-08-01
影响因子：
12.8
通讯作者：
Shao, Qixiang
中科院分区：
文献类型：
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作者：
Xie, Mengxiao;Wang, Jingzhe;Shao, Qixiang
调节性T（Treg）细胞亚群具有其特异性转录Foxp 3，是通过控制效应T（Teff）细胞应答来维持免疫稳态的独特细胞类型。虽然Treg/Teff紊乱的Treg细胞缺陷导致自身免疫性疾病是常见的;然而，确切的机制尚未完全揭示。在此，我们报道了miR-34 a可以通过靶向人和小鼠Foxp 3基因的3'非翻译区（3' UTR）来减弱其表达。类风湿性关节炎（RA）或系统性红斑狼疮（SLE）患者外周血单核细胞（PBMC）和CD 4（+）T细胞中的人miR-34 a增加，与一些炎症血清标志物（包括类风湿因子（RF）、抗链球菌溶血素抗体（阿索）、红细胞沉降率（ESR）和C反应蛋白（CRP）以及Th 17标志基因ROR γ t，但与FOXP 3的mRNA表达水平呈负相关。此外，与活化的CD 4（+）T细胞相比，小鼠miR-34 a水平在TGF-β诱导的Treg细胞中下调，但在体外诱导的Th 17细胞中上调。研究还表明，miR-34 a升高破坏体内Treg/Th 17平衡有助于胶原诱导的关节炎（CIA）小鼠发病机制的进展。此外，IL-6和TNF-α负责miR-34 a的上调和Foxp 3的下调，其通过加入NF-κ B/p65抑制剂BAY 11 -7082而逆转，因此表明NF-κ B/p65以miR-34 a依赖性方式抑制Foxp 3表达。最后，IL-6或TNF-α激活的p65可以与miR-34 a启动子结合并增强其活性，导致其转录上调。综上所述，我们发现，由炎性细胞因子如IL-6和TNF-α激活的NF-κ B通过调节miR-34 a表达来改善Foxp 3水平，这为自身免疫性疾病的发生提供了新的机制和治疗见解。
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 ROR gamma t, but inversely correlated with the mRNA expression levels of FOXP3. In addition, murine miR-34a levels were downregulated in TGF-beta-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-alpha were responsible for the upregulation of miR-34a and downregulation of Foxp3, which was reverted by the addition of NF-kappa B/p65 inhibitor BAY11-7082, thus indicating that NF-kappa B/p65 inhibited Foxp3 expression in an miR-34a-dependent manner. Finally, IL-6 or TNF-alpha-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-kappa B activated by inflammatory cytokines, such as IL-6 and TNF-alpha, ameliorates Foxp3 levels via regulating miR-34a expression, which provides a new mechanistic and therapeutic insight into the ongoing of autoimmune diseases.