All-Trans Retinoic Acid Induces CD4+CD25+FOXP3+Regulatory T Cells by Increasing FOXP3 Demethylation in Systemic Sclerosis CD4+T Cells
All-Trans Retinoic Acid Induces CD4+CD25+FOXP3+Regulatory T Cells by Increasing FOXP3 Demethylation in Systemic Sclerosis CD4+T Cells
复制标题
全反式视黄酸通过增加系统性硬化症 CD4 T 细胞中 FOXP3 去甲基化来诱导 CD4 CD25 FOXP3 调节性 T 细胞
DOI：
10.1155/2018/8658156
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发表时间：
2018
影响因子：
4.1
通讯作者：
Xiao Rong
中科院分区：
文献类型：
--
作者：
Sun Xiaohong;Xiao Yangfan;Zeng Zhuotong;Shi Yaqian;Tang Bingsi;Long Hai;Kanekura Takuro;Wang Jiucun;Wu Haijing;Zhao Ming;Lu Qianjin;Xiao Rong
背景资料。维甲酸(RA)是维生素A的活性代谢物，已有报道可改善系统性硬化症(SSC)患者的临床症状。然而，RA预防SSc的作用机制尚不清楚。调节性T细胞(Tregs)是具有免疫抑制活性的T细胞亚群。Tregs的数量和功能缺陷可能参与了SSC的免疫功能障碍。全反式维甲酸(ATRA)作用于人幼稚的CD4+细胞可以促进Tregs的成熟，增加Foxp3的稳定表达。本研究旨在探讨RA对SSCCD4+T细胞Tregs的作用及其可能的表观遗传学机制，以进一步了解RA对SSc的作用机制。分离自发性硬皮病患者外周血中的CD_4~+T细胞，用全反式维甲酸和/或转化生长因子-β(转化生长因子-β)处理。采用流式细胞仪检测外周血中CD4+CD25+FOXP3+Tregs百分率。用实时定量逆转录聚合酶链式反应和Western blotting分别检测Foxp3mRNA和蛋白水平。亚硫酸氢盐测序确定FOXP3近端启动子序列的甲基化状态。Tregs和FOXP3在SSC患者的CD4+T细胞中的表达随着ATRA的应答而增加。此外，联合应用全反式维甲酸和转化生长因子-β可增强上述作用。进一步研究发现，全反式维甲酸可通过下调FOXP3启动子甲基化水平，增加SSC CD4+T细胞FOXP3的表达。ATRA通过FOXP3启动子的去甲基化和FOXP3表达的激活，在SSC的CD4+T细胞中作为Treg反应的诱导者。这可能是全反式维甲酸的分子机制之一，因此维甲酸可用于治疗SSc。
Background. Retinoic acid (RA) is an active metabolite of vitamin A and has been reported to improve the clinical symptoms of patients with systemic sclerosis (SSc). However, the mechanism of RA in the prevention of SSc remains unclear. Regulatory T cells (Tregs) are a subpopulation of T cells with immunosuppressive activity. The quantitative and functional defects of Tregs may mediate the immune dysfunction in SSc. The addition of all‐trans retinoic acid (ATRA) to human naïve CD4+ cells could promote the maturation of Tregs and increase the stable expression of Foxp3. In this study, we explored the role of RA on Tregs in SSc CD4+ T cells and its possible epigenetic mechanisms, so as to further understand the mechanisms of RA on SSc.Methods. CD4+ T cells were isolated from peripheral blood of SSc and treated with or without ATRA and/or transforming growth factor‐β(TGF‐β). The percentage of CD4+CD25+FOXP3+ Tregs was counted by flow cytometry. FOXP3 mRNA and protein levels were measured by quantitative real‐time reverse transcriptase polymerase chain reaction and Western blotting, respectively. Bisulfite sequencing was performed to determine the methylation status of the FOXP3 proximal promoter sequences.Results. The expression of Tregs and FOXP3 in CD4+ T cells from patients with SSc increased in response to ATRA. Moreover, combined stimulation with ATRA and TGF‐βresulted in the enhancement of these effects. Further studies revealed that stimulation with ATRA increased the expression of FOXP3 in SSc CD4+ T cells by downregulating FOXP3 promoter methylation levels.Conclusions. ATRA acts as an inducer of Treg response in SSc CD4+ T cells via demethylation of the FOXP3 promoter and activation of FOXP3 expression. This may be one of the molecular mechanisms for ATRA, and therefore, RA can be used for the treatment of SSc.