2. Academic Validation
  3. 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

  • 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

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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