5-Aza-2-deoxycytidine alleviates the progression of primary biliary cholangitis by suppressing the FoxP3 methylation and promoting the Treg/Th17 balance
5-Aza-2-deoxycytidine alleviates the progression of primary biliary cholangitis by suppressing the FoxP3 methylation and promoting the Treg/Th17 balance
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5-Aza-2-deoxycytidine 通过抑制 FoxP3 甲基化和促进 Treg/Th17 平衡来缓解原发性胆汁性胆管炎的进展
DOI：
10.1016/j.intimp.2021.107820
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发表时间：
2021-06-02
影响因子：
5.6
通讯作者：
Yang, Jin-hui
中科院分区：
文献类型：
--
作者：
Jiang, Ting;Zhang, Hong-wei;Yang, Jin-hui
原发性胆汁性胆管炎(PBC)是一种常见的自身免疫性肝病，表现为CD4+T细胞的浸润和随后的胆管上皮细胞(BECs)的靶向性损伤。作为CD4亚群的重要组成部分，Treg/Th17轴在肝脏微环境中维持自身耐受和炎症之间的免疫平衡。然而，Treg/Th17轴在PBC中的作用和调控机制尚不清楚。在这项研究中，我们检测了PBC患者的Treg/Th17轴，发现PBC中Treg/Th17轴在转录和细胞水平上都是不平衡的，Treg是一个弱候选，这与PBC的进展有关。这种不平衡的Treg/Th17轴可能受到FoxP3高甲基化的影响，这与DNA甲基转移酶的升高有关。此外，还研究了5-氮杂-2-脱氧胞苷(DAC)介导的FoxP3去甲基化对PBC小鼠的影响。我们证实，DAC显著抑制了FoxP3甲基化，重建了Treg/Th17平衡，从而减轻了肝脏损伤和炎症。综上所述，我们的数据表明，DAC通过抑制FoxP3的DNA甲基化，重建平衡的Treg/Th17轴，在缓解PBC的进展中发挥积极作用。DAC可作为治疗PBC的新的抗炎策略的潜在候选者。
Primary biliary cholangitis (PBC) is a common autoimmune liver disease manifested by the infiltration of CD4+ T cells, and the subsequent targeted injury of biliary epithelial cells (BECs). As important components of CD4 subsets, the Treg/Th17 axis maintains an immunological balance between self-tolerance and inflammation in the liver microenvironment. However, the role and regulatory mechanism of the Treg/Th17 axis in PBC remain unclear. In this study, we examined the Treg/Th17 axis in PBC patients and found that the Treg/Th17 axis was imbalanced in PBC at both the transcriptional and cellular levels, with Treg being a weak candidate, which correlates with the PBC progression. This imbalanced Treg/Th17 axis was likely to be affected by the FoxP3 hypermethylation, which was related to the increase of DNA methyltransferase. Furthermore, the effect of 5-Aza2-deoxycytidine (DAC)-mediated FoxP3 demethylation on PBC mice was investigated. We verified that DAC significantly suppressed the FoxP3 methylation and rebuilt the Treg/Th17 balance, resulting in the alleviation of liver lesions and inflammation. Taken together, our data indicate that DAC plays a positive role in alleviating the progression of PBC through the inhibition of DNA methylation of FoxP3 to rebuild the balanced Treg/Th17 axis. DAC could be considered as a potential candidate for the development of new anti-inflammation strategies in the treatment of PBC.