Xia Haibo, Wu Yan, Zhao Jing, Li Wenqi, Lu Lu, Ma Huimin, Cheng Cheng, Sun Jing, Xiang Quanyong, Bian Tao, Liu Qizhan
Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China.
China International Cooperation Center for Environment and Human Health, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China.
Cell Biol Toxicol. 2022 Feb;38(1):167-183. doi: 10.1007/s10565-021-09585-1. Epub 2021 Mar 4.
Cigarette smoke (CS), a complex chemical indoor air pollutant, induces degradation of elastin, resulting in emphysema. Aberrant cross-talk between macrophages and bronchial epithelial cells is essential for the degradation of elastin that contributes to emphysema, in which extracellular vesicles (EVs) play a critical role. The formation of N6-methyladenosine (m6A) is a modification in miRNA processing, but its role in the development of emphysema remains unclear. Here, we established that production of excess mature microRNA-93 (miR-93) in bronchial epithelial cells via enhanced m6A modification was mediated by overexpressed methyltransferase-like 3 (METTL3) induced by CS. Mature miR-93 was transferred from bronchial epithelial cells into macrophages by EVs. In macrophages, miR-93 activated the JNK pathway by targeting dual-specificity phosphatase 2 (DUSP2), which elevated the levels of matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 12 (MMP12) and induced elastin degradation, leading to emphysema. These results demonstrate that METTL3-mediated formation of EV miR-93, facilitated by m6A, is implicated in the aberrant cross-talk of epithelium-macrophages, indicating that this process is involved in the smoking-related emphysema. EV miR-93 may use as a novel risk biomarker for CS-induced emphysema.
香烟烟雾（CS）是一种复杂的室内化学空气污染物，可导致弹性蛋白降解，进而引发肺气肿。巨噬细胞与支气管上皮细胞之间异常的相互作用对于导致肺气肿的弹性蛋白降解至关重要，其中细胞外囊泡（EVs）发挥着关键作用。N6-甲基腺苷（m6A）的形成是miRNA加工过程中的一种修饰，但其在肺气肿发展中的作用尚不清楚。在此，我们证实，CS诱导的过表达甲基转移酶样3（METTL3）介导了支气管上皮细胞中通过增强m6A修饰产生过量的成熟微小RNA-93（miR-93）。成熟的miR-93通过EVs从支气管上皮细胞转移至巨噬细胞。在巨噬细胞中，miR-93通过靶向双特异性磷酸酶2（DUSP2）激活JNK通路，从而提高基质金属蛋白酶9（MMP9）和基质金属蛋白酶12（MMP12）的水平并诱导弹性蛋白降解，导致肺气肿。这些结果表明，m6A促进的METTL3介导的EV miR-93形成与上皮细胞-巨噬细胞的异常相互作用有关，表明该过程参与了吸烟相关的肺气肿。EV miR-93可能用作CS诱导的肺气肿的新型风险生物标志物。
