GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 511436, China.
School of basic medicine sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Ecotoxicol Environ Saf. 2024 Sep 15;283:116793. doi: 10.1016/j.ecoenv.2024.116793. Epub 2024 Aug 1.
Biomass-related airborne fine particulate matter (PM2.5) is an important risk factor for chronic obstructive pulmonary disease (COPD). Macrophage polarization has been reported to be involved in PM2.5-induced COPD, but the dynamic characteristics and underlying mechanism of this process remain unclear. Our study established a PM2.5-induced COPD mouse model and revealed that M2 macrophages predominantly presented after 4 and 6 months of PM2.5 exposure, during which a notable increase in MMP12 was observed. Single cell analysis of lung tissues from COPD patients and mice further revealed that M2 macrophages were the dominant macrophage subpopulation in COPD, with MMP12 being involved as a hub gene. In vitro experiments further demonstrated that PM2.5 induced M2 polarization and increased MMP12 expression. Moreover, we found that PM2.5 increased IL-4 expression, STAT6 phosphorylation and nuclear translocation. Nuclear pSTAT6 then bound to the MMP12 promoter region. Furthermore, the inhibition of STAT6 phosphorylation effectively abrogated the PM2.5-induced increase in MMP12. Using a coculture system, we observed a significantly reduced level of E-cadherin in alveolar epithelial cells cocultured with PM2.5-exposed macrophages, while the decrease in E-cadherin was reversed by the addition of an MMP12 inhibitor to the co-culture system. Taken together, these findings indicated that PM2.5 induced M2 macrophage polarization and MMP12 upregulation via the IL-4/STAT6 pathway, which resulted in alveolar epithelial barrier dysfunction and excessive extracellular matrix (ECM) degradation, and ultimately led to COPD progression. These findings may help to elucidate the role of macrophages in COPD, and suggest promising directions for potential therapeutic strategies.
生物量相关的空气细颗粒物（PM2.5）是慢性阻塞性肺疾病（COPD）的一个重要危险因素。据报道，巨噬细胞极化参与了 PM2.5 诱导的 COPD，但这一过程的动态特征和潜在机制尚不清楚。我们的研究建立了 PM2.5 诱导的 COPD 小鼠模型，揭示了 PM2.5 暴露 4 个月和 6 个月后主要出现 M2 巨噬细胞，在此期间观察到 MMP12 显著增加。COPD 患者和小鼠肺组织的单细胞分析进一步表明，M2 巨噬细胞是 COPD 中的主要巨噬细胞亚群，MMP12 作为一个枢纽基因参与其中。体外实验进一步表明，PM2.5 诱导 M2 极化并增加 MMP12 表达。此外，我们发现 PM2.5 增加了 IL-4 的表达、STAT6 的磷酸化和核转位。核 pSTAT6 随后与 MMP12 启动子区域结合。此外，抑制 STAT6 磷酸化可有效阻断 PM2.5 诱导的 MMP12 增加。通过共培养系统，我们观察到与暴露于 PM2.5 的巨噬细胞共培养的肺泡上皮细胞中 E-钙黏蛋白水平显著降低，而在共培养系统中加入 MMP12 抑制剂可逆转 E-钙黏蛋白的降低。综上所述，这些发现表明，PM2.5 通过 IL-4/STAT6 途径诱导 M2 巨噬细胞极化和 MMP12 上调，导致肺泡上皮屏障功能障碍和细胞外基质（ECM）过度降解，最终导致 COPD 进展。这些发现可能有助于阐明巨噬细胞在 COPD 中的作用，并为潜在的治疗策略提供有前途的方向。
