The aberrant cross-talk of epithelium-macrophages via METTL3-regulated extracellular vesicle miR-93 in smoking-induced emphysema
The aberrant cross-talk of epithelium-macrophages via METTL3-regulated extracellular vesicle miR-93 in smoking-induced emphysema
复制标题
吸烟引起的肺气肿中上皮-巨噬细胞通过 METTL3 调节的细胞外囊泡 miR-93 的异常串扰
DOI：
10.1007/s10565-021-09585-1
复制
发表时间：
2021
影响因子：
6.1
通讯作者：
Qizhan Liu
中科院分区：
文献类型：
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作者：
Haibo Xia;Yan Wu;Jing Zhao;Wenqi Li;Lu Lu;Huimin Ma;Cheng Cheng;Jing Sun;Quanyong Xiang;Tao Bian;Qizhan Liu
香烟烟雾（CS）是一种复杂的化学室内空气污染物，可引起弹性蛋白降解，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的降解是必不可少的，其中细胞外囊泡（EV）起关键作用。N6-甲基腺苷（m6 A）的形成是miRNA加工过程中的一种修饰，但其在肺气肿发生中的作用仍不清楚。在这里，我们确定了通过增强m6 A修饰在支气管上皮细胞中产生过量成熟microRNA-93（miR-93）是由CS诱导的过表达甲基转移酶样3（methyltransferase-like 3，简称MTL 3）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（DUSP 2）激活JNK通路，从而升高基质金属蛋白酶9（MMP 9）和基质金属蛋白酶12（MMP 12）的水平，并诱导弹性蛋白降解，导致肺气肿。这些结果表明，由m6 A促进的胃L3介导的EV miR-93的形成涉及上皮-巨噬细胞的异常串扰，表明该过程涉及吸烟相关的肺气肿。EV miR-93可用作CS诱导的肺气肿的新风险生物标志物。
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