Targeted inhibition of m6A demethylase FTO by FB23 attenuates allergic inflammation in the airway epithelium

被引:4
作者
Lian, Zexuan [1 ]
Chen, Ruchong [1 ]
Xian, Mo [1 ]
Huang, Peiying [1 ]
Xu, Jiahan [1 ]
Xiao, Xiaojun [2 ]
Ning, Xiaoping [1 ]
Zhao, Jin [3 ]
Xie, Jianlei [3 ]
Duan, Jielin [1 ]
Li, Bizhou [1 ]
Wang, Wanjun [1 ]
Shi, Xu [1 ]
Wang, Xinru [1 ]
Jia, Nan [1 ]
Chen, Xuepeng [4 ]
Li, Jing [1 ]
Yang, Zhaowei [1 ]
机构
[1] Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Hlth, Natl Clin Res Ctr Resp Dis,Natl Ctr Resp Med,Dept, Guangzhou 510182, Guangdong, Peoples R China
[2] Shenzhen Univ, Allergy Div, State Key Lab Resp Dis, Shenzhen Key Lab Allergy & Immunol, Shenzhen, Guangdong, Peoples R China
[3] Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Hlth, Natl Ctr Resp Med,Natl Clin Res Ctr Resp Dis,State, Guangzhou, Guangdong, Peoples R China
[4] Guangzhou Med Univ, GMU GIBH Joint Sch Life Sci, Guangdong Hong Kong Macau Joint Lab Cell Fate Regu, Guangzhou Natl Lab, Guangzhou 510005, Peoples R China
关键词
allergic inflammation; asthma; epithelial cells; FTO; m6A; ASTHMA; MUSCLE; M(6)A; RNA; MECHANISMS; GENE;
D O I
10.1096/fj.202400545R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Epithelial cells play a crucial role in asthma, contributing to chronic inflammation and airway hyperresponsiveness. m6A modification, which involves key proteins such as the demethylase fat mass and obesity-associated protein (FTO), is crucial in the regulation of various diseases, including asthma. However, the role of FTO in epithelial cells and the development of asthma remains unclear. In this study, we investigated the demethylase activity of FTO using a small-molecule inhibitor FB23 in epithelial cells and allergic inflammation in vivo and in vitro. We examined the FTO-regulated transcriptome-wide m6A profiling by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq under FB23 treatment and allergic inflammation conditions. Immunofluorescence staining was performed to assess the tissue-specific expression of FTO in asthmatic bronchial mucosa. We demonstrated that FB23 alleviated allergic inflammation in IL-4/IL-13-treated epithelial cells and house dust mite (HDM)-induced allergic airway inflammation mouse model. The demethylase activity of FTO contributed to the regulation of TNF-alpha signaling via NF-kappa B and epithelial-mesenchymal transition-related pathways under allergic inflammation conditions in epithelial cells. FTO was expressed in epithelial, submucosal gland, and smooth muscle cells in human bronchial mucosa. In conclusion, FB23-induced inhibition of FTO alleviates allergic inflammation in epithelial cells and HDM-induced mice, potentially through diverse cellular processes and epithelial-mesenchymal transition signaling pathways, suggesting that FTO is a potential therapeutic target in asthma management.
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页数:15
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