2. Academic Validation
  3. Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis

  • Cell Commun Signal. 2024 Jul 17;22(1):364. doi: 10.1186/s12964-024-01746-z.
Yue Dong # 1 2 3 4,  Ying Dong # 4,  Chengyue Zhu # 1 2 3,  Lan Yang 5,  Hanlin Wang 4,  Junqing Li 1 2,  Zixuan Zheng 6,  Hanwei Zhao 6,  Wanji Xie 7,  Meiting Chen 8,  Zhijun Jie 1 2,  Jia Li 4 5 8 9 10,  Yi Zang 11,  Jindong Shi 12 13
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
  • 2 Center of Community-Based Health Research, Fudan University, Shanghai, China.
  • 3 Lingang Laboratory, 100-19 Banxia Road, Pudong New District, Shanghai, 200120, China.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 6 Department of General Medicine, Zhuanqiao Community Healthcare Service Center of Minhang District, Shanghai, China.
  • 7 Department of General Medicine, Hongqiao Community Healthcare Service Center of Minhang District, Shanghai, China.
  • 8 Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
  • 9 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, China.
  • 10 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China.
  • 11 Lingang Laboratory, 100-19 Banxia Road, Pudong New District, Shanghai, 200120, China. yzang@lglab.ac.cn.
  • 12 Department of Respiratory and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China. shijindong@fudan.edu.cn.
  • 13 Center of Community-Based Health Research, Fudan University, Shanghai, China. shijindong@fudan.edu.cn.
  • # Contributed equally.
PMID: 39014433 DOI: 10.1186/s12964-024-01746-z
Abstract

Background: Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C-C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies.

Methods: This study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis.

Results: Elevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a CCR2 Inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD.

Conclusions: The study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology.

Keywords

Bronchial epithelial cells; Chronic obstructive pulmonary disease; C–C chemokine receptor type 2; C–C motif chemokine ligand 2; Macrophage.

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