State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.
State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University, Shenzhen Key Laboratory of Allergy and Immunology, Shenzhen University, Shenzhen, Guangdong, P.R. China.
FASEB J. 2024 Aug 15;38(15):e23846. doi: 10.1096/fj.202400545R.
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-α signaling via NF-κB 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.
上皮细胞在哮喘中发挥着至关重要的作用，它们参与慢性炎症和气道高反应性的发生。m6A 修饰涉及关键蛋白，如去甲基酶脂肪量和肥胖相关蛋白（FTO），在包括哮喘在内的各种疾病的调控中起着关键作用。然而，FTO 在上皮细胞中的作用以及其在哮喘中的发展机制尚不清楚。在这项研究中，我们使用小分子抑制剂 FB23 在体外和体内研究了 FTO 在上皮细胞中的去甲基酶活性以及在过敏性炎症中的作用。我们通过 MeRIP-seq 和 RNA-seq 检测了 FB23 处理和过敏性炎症条件下 FTO 调节的转录组范围内 m6A 谱。通过免疫荧光染色评估了 FTO 在哮喘支气管黏膜中的组织特异性表达。我们证实 FB23 可减轻 IL-4/IL-13 处理的上皮细胞中的过敏性炎症和屋尘螨（HDM）诱导的过敏性气道炎症小鼠模型中的炎症。在过敏性炎症条件下，FTO 的去甲基酶活性通过 NF-κB 和上皮-间充质转化相关途径调节 TNF-α 信号通路。FTO 在人支气管黏膜的上皮细胞、黏膜下腺和平滑肌细胞中表达。综上所述，FB23 诱导的 FTO 抑制减轻了上皮细胞中的过敏性炎症和 HDM 诱导的炎症，可能通过多种细胞过程和上皮-间充质转化信号通路发挥作用，这表明 FTO 是哮喘管理中一种有潜力的治疗靶点。
