Protein Arginine Methyltransferase 5 Inhibition Upregulates Foxp3(+) Regulatory T Cells Frequency and Function during the Ulcerative Colitis.
Protein Arginine Methyltransferase 5 Inhibition Upregulates Foxp3(+) Regulatory T Cells Frequency and Function during the Ulcerative Colitis.
复制标题
蛋白质精氨酸甲基转移酶 5 抑制上调 Foxp3( ) 调节性 T 细胞在溃疡性结肠炎期间的频率和功能
DOI：
10.3389/fimmu.2017.00596
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发表时间：
2017
影响因子：
7.3
通讯作者：
Shen L
中科院分区：
文献类型：
--
作者：
Zheng Y;Huang L;Ge W;Yang M;Ma Y;Xie G;Wang W;Bian B;Li L;Nie H;Shen L
溃疡性结肠炎(UC)的发病机制与免疫反应失衡有关，炎性T细胞和Foxp3+调节性T细胞(Tregs)之间的平衡在肠道内稳态中起重要作用。蛋白精氨酸甲基转移酶(PRMTs)调节染色质重塑和基因表达。在这里，我们研究了抑制PRMTs是否影响小鼠结肠炎和炎症性肠病患者的发病机制，并进一步探讨其潜在机制。在这项研究中，我们发现蛋白精氨酸N-甲基转移酶抑制剂1(AMI-1)治疗增加了Tregs频率，增加了功能，并降低了结肠炎的发生率。过继移植经治疗的Tregs可降低结肠炎的发生率。结肠炎与局部PRMT5表达增加有关，这种表达可被AMI-1治疗抑制。此外，PRMT5基因敲除的T细胞对转化生长因子β有更好的反应，并通过减少DNA甲基转移酶1的表达促进Treg的分化。PRMT5还增强了H3K27me3和DNMT1与Foxp3启动子的结合，从而抑制了Tregs的分化。此外，在Tregs诱导过程中，PRMT5基因敲除导致Foxp3启动子甲基化减少。在UC患者中，PRMT5的表达与Tregs呈负相关，下调PRMT5的表达使Tregs频率增加，降低肿瘤坏死因子α、IL-6和IL-13的水平。我们的研究概述了PRMT5对Tregs发育和功能的新调节。降低PRMT5表达的策略可能对控制UC有潜在的治疗作用。
Ulcerative colitis (UC) pathogenesis is related to imbalance of immune responses, and the equilibrium between inflammatory T cells and Foxp3+ regulatory T cells (Tregs) plays an important role in the intestinal homeostasis. Protein arginine methyltransferases (PRMTs) regulate chromatin remodeling and gene expression. Here, we investigated whether inhibition of PRMTs affects colitis pathogenesis in mice and inflammatory bowel disease patients and further explored the underlying mechanisms. In this study, we found that protein arginine N-methyltransferase inhibitor 1 (AMI-1) treatments increased Tregs frequency, function, and reduced colitis incidence. Adoptive transfer of AMI-1-treated Tregs could reduce the colitis incidence. Colitis was associated with increased local PRMT5 expression, which was inhibited by AMI-1 treatment. Additionally, PRMT5 knockdown T cells produced a better response to TGFβ and promoted Tregs differentiation through decreased DNA methyltransferase 1 (DNMT1) expression. PRMT5 also enhanced H3K27me3 and DNMT1 binding to Foxp3 promoter, which restricted Tregs differentiation. Furthermore, PRMT5 knockdown led to decreased Foxp3 promoter methylation during Tregs induction. PRMT5 expression had a negative relationship with Tregs in UC patients, knockdown of PRMT5 expression increased Tregs frequency and decreased TNFα, IL-6, and IL-13 levels. Our study outlines a novel regulation of PRMT5 on Tregs development and function. Strategies to decrease PRMT5 expression might have therapeutic potential to control UC.