2. Academic Validation
  3. Involvement of M2 macrophages polarization in PM2.5-induced COPD by upregulating MMP12 via IL4/STAT6 pathway

Involvement of M2 macrophages polarization in PM2.5-induced COPD by upregulating MMP12 via IL4/STAT6 pathway

  • Ecotoxicol Environ Saf. 2024 Aug 1:283:116793. doi: 10.1016/j.ecoenv.2024.116793.
Xiaolan Guo 1,  Siqi Yang 1,  Huijuan Zhu 1,  Fengdong Liu 1,  Kai Li 1,  Guojun Li 1,  Yuyin Lin 1,  Hongjiao Yu 1,  Wenxi Qiu 1,  Hao Xu 1,  Qiao Liu 2,  Xinran Xie 1,  Yaowei Sun 1,  Peiji Zheng 1,  Bingjie Chen 1,  Zihan Liu 1,  Xiaopeng Yuan 3,  Shuyi Peng 4,  Xinhui Bi 4,  Jingwen Yang 5,  Ning-Yi Shao 6,  Jianwei Dai 7
Affiliations

Affiliations

  • 1 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.
  • 2 School of basic medicine sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China.
  • 3 The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 510000, China.
  • 4 State Key Laboratory of Organic Geochemistry, Guangdong Provincial Key Laboratory of Environmental Protection and Resources Utilization, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510000, China.
  • 5 The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan 511510, China.
  • 6 Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau Special Administrative Region of China 999078, China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR 999078, China. Electronic address: nshao@um.edu.mo.
  • 7 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. Electronic address: daijw@gzhmu.edu.cn.
PMID: 39094453 DOI: 10.1016/j.ecoenv.2024.116793
Abstract

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.

Keywords

COPD; IL-4/STAT6 pathway; M2 macrophage polarization; MMP12; PM2.5.

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