Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, China.
Department of Pulmonary and Critical Care Medicine, Sichuan Friendship Hospital, Chengdu, 610000, China.
Environ Pollut. 2022 Sep 1;308:119607. doi: 10.1016/j.envpol.2022.119607. Epub 2022 Jun 16.
Fine particulate matter 2.5 (PM2.5) exposure leads to the progress of pulmonary disease. It has been reported that N6-methyladenosine (m6A) modification was involved in various biological processes and diseases. However, the critical role of m6A modification in pulmonary disease during PM2.5 exposure remains elusive. Here, we revealed that lung inflammation and mucus production caused by PM2.5 were associated with m6A modification. Both in vivo and in vitro assays demonstrated that PM2.5 exposure elevated the total level of m6A modification as well as the methyltransferase like 3 (METTL3) expression. Integration analysis of m6A RNA immunoprecipitation-seq (meRIP-seq) and RNA-seq discovered that METTL3 up-regulated the expression level and the m6A modification of Interleukin 24 (IL24). Importantly, we explored that the stability of IL24 mRNA was enhanced due to the increased m6A modification. Moreover, the data from qRT-PCR showed that PM2.5 also increased YTH N6-Methyladenosine RNA Binding Protein 1 (YTHDF1) expression, and the up-regulated YTHDF1 augmented IL24 mRNA translation efficiency. Down-regulation of Mettl3 reduced Il24 expression and ameliorated the pulmonary inflammation and mucus secretion in mice exposed to PM2.5. Taken together, our finding provided a comprehensive insight for revealing the significant role of m6A regulators in the lung injury via METTL3/YTHDF1-coupled epitranscriptomal regulation of IL24.
细颗粒物 2.5（PM2.5）暴露导致肺部疾病的进展。据报道，N6-甲基腺苷（m6A）修饰参与了各种生物过程和疾病。然而，PM2.5 暴露时 m6A 修饰在肺部疾病中的关键作用仍不清楚。在这里，我们揭示了 PM2.5 引起的肺部炎症和粘液产生与 m6A 修饰有关。体内和体外实验均表明，PM2.5 暴露会增加 m6A 修饰的总水平以及甲基转移酶样 3（METTL3）的表达。m6A RNA 免疫沉淀测序（meRIP-seq）和 RNA-seq 的整合分析发现，METTL3 上调了白细胞介素 24（IL24）的表达水平和 m6A 修饰。重要的是，我们探索了由于 m6A 修饰增加，IL24 mRNA 的稳定性增强。此外，qRT-PCR 的数据表明，PM2.5 还增加了 YTH N6-甲基腺苷 RNA 结合蛋白 1（YTHDF1）的表达，而上调的 YTHDF1 增强了 IL24 mRNA 的翻译效率。下调 Mettl3 减少了 Il24 的表达，并改善了暴露于 PM2.5 的小鼠的肺部炎症和粘液分泌。总之，我们的研究结果为揭示 m6A 调节剂在通过 METTL3/YTHDF1 偶联的转录后调控 IL24 介导的肺部损伤中的重要作用提供了全面的认识。
