MBD2 mediates Th17 cell differentiation by regulating MINK1 in Th17-dominant asthma

Zhifeng Chen; Yulin Shang; Yu Yuan; Yi He; Binaya Wasti; Wentao Duan; Ruoyun Ouyang; Jingsi Jia; Bing Xiao; Dongshan Zhang; Xiufeng Zhang; Jianmin Li; Bolin Chen; Yi Liu; Qingping Zeng; Xiaoying Ji; Libing Ma; Shaokun Liu; Xudong Xiang

doi:10.3389/fgene.2022.959059

MBD2 mediates Th17 cell differentiation by regulating MINK1 in Th17-dominant asthma

Front Genet. 2022 Oct 11:13:959059. doi: 10.3389/fgene.2022.959059. eCollection 2022.

Authors

Zhifeng Chen¹, Yulin Shang², Yu Yuan¹, Yi He¹, Binaya Wasti¹, Wentao Duan¹, Ruoyun Ouyang¹, Jingsi Jia³, Bing Xiao³, Dongshan Zhang³, Xiufeng Zhang⁴, Jianmin Li⁵, Bolin Chen⁵, Yi Liu⁶, Qingping Zeng⁷, Xiaoying Ji⁸, Libing Ma⁹, Shaokun Liu¹, Xudong Xiang³

Affiliations

¹ Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Ophthalmology and Otorhinolaryngology, Zigui County Traditional Chinese Medicine Hospital, Zigui, Hubei, China.
³ Department of Emergency, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Department of Respiratory Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China.
⁵ Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital, Changsha, Hunan, China.
⁶ Department of Respiratory Medicine, Zhuzhou City Central Hospital, Zhuzhou, Hunan, China.
⁷ Department of Respiratory and Critical Care Medicine, Longshan County People's Hospital, Longshan, Hunan, China.
⁸ Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
⁹ Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.

Abstract

Objectives: .Asthma is a highly heterogeneous disease, and T-helper cell type 17 (Th17) cells play a pathogenic role in the development of non-T2 severe asthma. Misshapen like kinase 1 (MINK1) is involved in the regulation of Th17 cell differentiation, but its effect on severe asthma remains unclear. Our previous studies showed that methyl-CpG binding domain protein 2 (MBD2) expression was significantly increased in patients with Th17 severe asthma and could regulate Th17 cell differentiation. The aim of this study was to investigate how MBD2 interacts with MINK1 to regulate Th17 cell differentiation in Th17-dominant asthma. Materials and methods: Female C57BL/6 mice and bronchial epithelial cells (BECs) were used to establish mouse and cell models of Th17-dominant asthma, respectively. Flow cytometry was used to detect Th17 cell differentiation, and the level of IL-17 was detected by enzyme-linked immunosorbent assay (ELISA). Western blot and quantitative real-time PCR (qRT-PCR) were used to detect MBD2 and MINK1 expression. To investigate the role of MBD2 and MINK1 in Th17 cell differentiation in Th17-dominant asthma, the MBD2 and MINK1 genes were silenced or overexpressed by small interfering RNA and plasmid transfection. Results: Mouse and BEC models of Th17-dominant asthma were established successfully. The main manifestations were increased neutrophils in BALF, airway hyperresponsiveness (AHR), activated Th17 cell differentiation, and high IL-17 levels. The expression of MBD2 in lung tissues and BECs from the Th17-dominant asthma group was significantly increased, while the corresponding expression of MINK1 was significantly impaired. Through overexpression or silencing of MBD2 and MINK1 genes, we have concluded that MBD2 and MINK1 regulate Th17 cell differentiation and IL-17 release. Interestingly, MBD2 was also found to negatively regulate the expression of MINK1. Conclusion: Our findings have revealed new roles for MBD2 and MINK1, and provide new insights into epigenetic regulation of Th17-dominant asthma, which is dominated by neutrophils and Th17 cells. This study could lead to new therapeutic targets for patients with Th17-dominant asthma.

Keywords: Th17-dominant asthma; bronchial epithelial cells; methyl-cpg binding domain protein 2; misshapen like kinase 1; t-helper cell type 17 cells.