5-Aza-2-deoxycytidine alleviates the progression of primary biliary cholangitis by suppressing the FoxP3 methylation and promoting the Treg/Th17 balance

•Imbalanced Treg/Th17 axis shapes hepatic inflammatory microenvironment in PBC.•FoxP3 hypermethylation happened in PBC, leading to the imbalanced Treg/Th17 axis.•Increased DNMT1 and decreased IDH1 enhance the FoxP3 methylation.•Demethylation of FoxP3 rebalances Treg/Th17 axis, inhibiting inflammatio...

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Veröffentlicht in:International immunopharmacology 2021-07, Vol.96, p.107820, Article 107820
Hauptverfasser: Jiang, Ting, Zhang, Hong-wei, Wen, Yan-ping, Yin, Yue-shan, Yang, Li-hong, Yang, Jing, Lan, Tian, Tang, Cheng-wei, Yu, Jian-kun, Tai, Wen-lin, Yang, Jin-hui
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Sprache:eng
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Zusammenfassung:•Imbalanced Treg/Th17 axis shapes hepatic inflammatory microenvironment in PBC.•FoxP3 hypermethylation happened in PBC, leading to the imbalanced Treg/Th17 axis.•Increased DNMT1 and decreased IDH1 enhance the FoxP3 methylation.•Demethylation of FoxP3 rebalances Treg/Th17 axis, inhibiting inflammation of PBC.•DAC inhibits FoxP3 methylation and verifies the therapeutic potential on PBC. 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-Aza-2-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.
ISSN:1567-5769
1878-1705
DOI:10.1016/j.intimp.2021.107820