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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All human samples procedures were approved by the Ethics Committee of Wuxi People’s Hospital affiliated with Nanjing Medical University. All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee at Nanjing Medical University.
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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