Site-specific Atg13 methylation-mediated autophagy regulates epithelial inflammation in PM2.5-induced pulmonary fibrosis.
Site-specific Atg13 methylation-mediated autophagy regulates epithelial inflammation in PM2.5-induced pulmonary fibrosis.
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DOI：
10.1016/j.jhazmat.2023.131791
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发表时间：
2023-06
影响因子：
13.6
通讯作者：
Jie Ning;Z. Pei;Mengruo Wang;Huaifang Hu;Meiyu Chen;Qingping Liu;Mengqi Wu;Peihao Yang;Zi-han Geng;Jie Zheng;Zhe Du;Wentao Hu;Qian Wang;Yaxian Pang;Lei Bao;Yu-jie Niu;S. Leng;Rong Zhang
中科院分区：
文献类型：
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作者：
Jie Ning;Z. Pei;Mengruo Wang;Huaifang Hu;Meiyu Chen;Qingping Liu;Mengqi Wu;Peihao Yang;Zi-han Geng;Jie Zheng;Zhe Du;Wentao Hu;Qian Wang;Yaxian Pang;Lei Bao;Yu-jie Niu;S. Leng;Rong Zhang
细颗粒物（PM2.5）增加了肺纤维化的风险。然而，肺上皮细胞在肺纤维化中的调控机制仍不清楚。在这里，我们开发了PM2.5暴露的肺上皮细胞和小鼠模型，以研究自噬在肺上皮介导炎症和肺纤维化中的作用。PM2.5暴露可诱导肺上皮细胞自噬，进而通过激活NF-κB/NLRP 3信号通路驱动肺纤维化。PM2.5下调ALKBH 5蛋白表达促进肺上皮细胞Atg 13 mRNA 767位点m6 A修饰Atg 13介导的ULK复合物在PM2.5处理的上皮细胞中正向调节自噬和炎症。小鼠中ALKBH 5的敲除进一步加速了ULK复合物调节的自噬、炎症和肺纤维化。因此，我们的研究结果表明，Atg 13 mRNA上的位点特异性m6 A甲基化以自噬依赖的方式调节PM2.5暴露后上皮炎症驱动的肺纤维化，并为PM2.5诱导的肺纤维化提供了靶向干预策略。
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.