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.

Graphical abstract

中文翻译：

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吸烟引起的肺气肿中通过 METTL3 调节的细胞外囊泡 miR-93 的上皮-巨噬细胞的异常串扰

香烟烟雾 (CS) 是一种复杂的化学室内空气污染物，可诱导弹性蛋白降解，导致肺气肿。巨噬细胞和支气管上皮细胞之间的异常串扰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 (EV) 起着关键作用。N6-甲基腺苷 (m6A) 的形成是 miRNA 加工的一种修饰，但其在肺气肿发展中的作用仍不清楚。在这里，我们确定通过增强的 m6A 修饰在支气管上皮细胞中产生过量的成熟 microRNA-93 (miR-93) 是由 CS 诱导的过表达甲基转移酶样 3 (METTL3) 介导的。成熟的 miR-93 通过 EV 从支气管上皮细胞转移到巨噬细胞中。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，由 m6A 促进的 METTL3 介导的 EV miR-93 的形成与上皮-巨噬细胞的异常串扰有关，表明该过程与吸烟相关的肺气肿有关。EV miR-93 可用作 CS 诱导的肺气肿的新型风险生物标志物。与上皮 - 巨噬细胞的异常串扰有关，表明该过程与吸烟相关的肺气肿有关。EV miR-93 可用作 CS 诱导的肺气肿的新型风险生物标志物。与上皮 - 巨噬细胞的异常串扰有关，表明该过程与吸烟相关的肺气肿有关。EV miR-93 可用作 CS 诱导的肺气肿的新型风险生物标志物。

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