Abstract
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.
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The authors thank Donald L. Hill (University of Alabama at Birmingham, USA), an experienced, English-speaking scientific editor, for editing.
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This work was supported by the Natural Science Foundations of China (81973085, 81803276, 81973005), the Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (BJ2020006), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (2019).
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Haibo Xia and Yan Wu designed and wrote the manuscript; Haibo Xia, Yan Wu, and Jing Zhao performed in vivo experiments; Haibo Xia and Jing Zhao performed in vitro experiments; Wenqi li, Lu Lu and Huimin Ma analyzed the data; Tao Bian and Qizhan Liu assisted with the manuscript revision; and Quanyong Xiang and Qizhan Liu supervised the study.
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Highlights
1. CSE increases levels of METTL3 and miR-93 with a dose-dependent manner in HBE cells.
2. CSE promotes miR-93 maturation via METTL3-mediated m6A modification in HBE cells.
3. CS induces the degradation of elastin in lung tissue due to elevation of MMP9 and MMP12 in macrophages.
4. EV miR-93 mediates the aberrant cross-talk of epithelium–macrophages in CS-induced emphysema.
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Xia, H., Wu, Y., Zhao, J. et al. The aberrant cross-talk of epithelium–macrophages via METTL3-regulated extracellular vesicle miR-93 in smoking-induced emphysema. Cell Biol Toxicol 38, 167–183 (2022). https://doi.org/10.1007/s10565-021-09585-1
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DOI: https://doi.org/10.1007/s10565-021-09585-1