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

  • Int Immunopharmacol. 2021 Jul:96:107820. doi: 10.1016/j.intimp.2021.107820.
Ting Jiang  1 ,  Hong-Wei Zhang  2 ,  Yan-Ping Wen  3 ,  Yue-Shan Yin  1 ,  Li-Hong Yang  1 ,  Jing Yang  1 ,  Tian Lan  4 ,  Cheng-Wei Tang  4 ,  Jian-Kun Yu  5 ,  Wen-Lin Tai  6 ,  Jin-Hui Yang  7
Affiliations
  • 1. Digestive Diseases Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 2. The Central Laboratory, Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, China.
  • 3. Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 4. Digestive Diseases Department, West China Hospital, Sichuan University, Chengdu, China.
  • 5. The Central Laboratory, Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, China. Electronic address: [email protected].
  • 6. Clinical Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China. Electronic address: [email protected].
  • 7. Digestive Diseases Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, China. Electronic address: [email protected].
PMID: 34162167 DOI: 10.1016/j.intimp.2021.107820
Abstract

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.

Keywords
Forkhead box protein 3; Methylation; Primary biliary cholangitis; Regulatory T cells; T helper 17 cells.
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