Site-specific Atg13 methylation-mediated autophagy regulates epithelial inflammation in PM2.5-induced pulmonary fibrosis

• Published in: Journal of hazardous materials 2023-09, Vol.457, p.131791-131791, Article 131791
• Main Authors: Ning, Jie, Pei, Zijie, Wang, Mengruo, Hu, Huaifang, Chen, Meiyu, Liu, Qingping, Wu, Mengqi, Yang, Peihao, Geng, Zihan, Zheng, Jie, Du, Zhe, Hu, Wentao, Wang, Qian, Pang, Yaxian, Bao, Lei, Niu, Yujie, Leng, Shuguang, Zhang, Rong
• Format: Article
• Language: English
• Subjects: Animals; Atg13; Autophagy; Epithelial autophagy; Inflammation - chemically induced; Methylation; Mice; Mice, Knockout; Particulate Matter - toxicity; PM2.5; Pulmonary fibrosis; Pulmonary Fibrosis - chemically induced; RNA, Messenger; ULK complex
• ISSN: 0304-3894; 1873-3336
• DOI: 10.1016/j.jhazmat.2023.131791

Fine particulate matters (PM2.5) increased the risk of pulmonary fibrosis. However, the regulatory mechanisms of lung epithelium in pulmonary fibrosis remained elusive. Here we developed PM2.5-exposure lung epithelial cells and mice models to investigate the role of autophagy in lung epithelia mediating inflammation and pulmonary fibrosis. PM2.5 exposure induced autophagy in lung epithelial cells and then drove pulmonary fibrosis by activation of NF-κB/NLRP3 signaling pathway. PM2.5-downregulated ALKBH5 protein expression promotes m6A modification of Atg13 mRNA at site 767 in lung epithelial cells. Atg13-mediated ULK complex positively regulated autophagy and inflammation in epithelial cells with PM2.5 treatment. Knockout of ALKBH5 in mice further accelerated ULK complex-regulated autophagy, inflammation and pulmonary fibrosis. Thus, our results highlighted that site-specific m6A methylation on Atg13 mRNA regulated epithelial inflammation-driven pulmonary fibrosis in an autophagy-dependent manner upon PM2.5 exposure, and it provided target intervention strategies towards PM2.5-induced pulmonary fibrosis. [Display omitted] •Inhibition of ALKBH5 promotes site-specific m6A modification of Atg13 mRNA upon PM2.5 exposure.•PM2.5 exposure induces ULK complex by upregulating Atg13 mRNA methylation at site 767.•Atg13-mediated ULK complex activates lung epithelial autophagy after PM2.5 exposure.•Autophagy-dependent epithelial inflammation caused by PM2.5 drives pulmonary fibrosis.