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  3. Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy

Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy

  • Cell Mol Immunol. 2025 Jul;22(7):776-790. doi: 10.1038/s41423-025-01288-5.
Shifeng Li 1,  Hong Xu 2,  Shupeng Liu 3,  Jinkun Hou 1 4 5,  Yueyin Han 1 4,  Chen Li 1 5,  Yupeng Li 1 6,  Gaigai Zheng 3,  Zhongqiu Wei 7,  Fang Yang 3,  Shuwei Gao 1 5,  Shiyao Wang 1 5,  Jing Geng 8 9,  Huaping Dai 10 11 12,  Chen Wang 13 14
Affiliations

Affiliations

  • 1 National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China.
  • 2 Health Science Center, Hebei Key Laboratory of Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei, China.
  • 3 School of Public Health, Hebei Key Laboratory of Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei, China.
  • 4 Peking Union Medical College, Beijing, China.
  • 5 Immune Dysfunction and Pulmonary Fibrosis Joint Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
  • 6 Second Affiliated Hospital of Harbin Medical University, Respiratory and Critical Care Medicine, Harbin, Heilongjiang, China.
  • 7 Basic Medical College, Hebei Key Laboratory of Organ Fibrosis, North China University of Science and Technology, Tangshan, Hebei, China.
  • 8 National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China. jing_geng@foxmail.com.
  • 9 Immune Dysfunction and Pulmonary Fibrosis Joint Laboratory for Clinical Medicine, Capital Medical University, Beijing, China. jing_geng@foxmail.com.
  • 10 National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China. daihuaping@ccmu.edu.cn.
  • 11 Peking Union Medical College, Beijing, China. daihuaping@ccmu.edu.cn.
  • 12 Immune Dysfunction and Pulmonary Fibrosis Joint Laboratory for Clinical Medicine, Capital Medical University, Beijing, China. daihuaping@ccmu.edu.cn.
  • 13 National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China. cyh-birm@263.net.
  • 14 Peking Union Medical College, Beijing, China. cyh-birm@263.net.
PMID: 40389600 DOI: 10.1038/s41423-025-01288-5
Abstract

Monocyte-derived macrophages (MoMacs) are the most important effector cells that cause pulmonary fibrosis. However, the characteristics of MoMac differentiation in silicosis and the mechanisms by which MoMacs affect the progression of pulmonary fibrosis remain unclear. Integration of single-cell and spatial transcriptomic analyses revealed that the silicosis niche was occupied by a subset of MoMacs, identified as Spp1hiMacs, which remain in an immature transitional state of differentiation during silicosis. This study investigated the mechanistic foundations of mitochondrial damage induced by the lipoprotein-associated Phospholipase A2 (Lp-PLA2, encoded by Pla2g7)-acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1)-cardiolipin (CL) signaling pathway, which interferes with Spp1hiMac differentiation. We demonstrated that in SiO2-induced MoMacs, Lp-PLA2 induces abnormal CL acylation through the activation of ALCAT1, resulting in impaired mitochondrial localization of PINK1 and LC3B and mitochondrial Autophagy defects. Simultaneously, lysosomal dysfunction causes the release of the lysosomal protein Cathepsin B into the cytoplasm, which involves M1 and M2 macrophage polarization and the activation of proinflammatory and profibrotic pathways. Furthermore, we assessed the efficacy of the Lp-PLA2 inhibitor darapladib in ameliorating silica-induced pulmonary fibrosis in a murine model. Our findings enhance our understanding of silicosis pathogenesis and offer promising opportunities for developing targeted therapies to mitigate fibrotic progression and maintain lung function in affected individuals.

Keywords

Cardiolipin; Lipoprotein-associated phospholipase A2; Mitophagy; Monocyte-derived macrophages; Pulmonary fibrosis.

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