MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis
Fibrotic hypersensitivity pneumonitis (FHP) is a fatal interstitial pulmonary disease with limited treatment options. Lung macrophages are a heterogeneous cell population that exhibit distinct subsets with divergent functions, playing pivotal roles in the progression of pulmonary fibrosis. However,...
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| Format: | Article |
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Elsevier
2024-02-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824000148 |
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| author | Dan Peng Juan Li Yin Li Lingling Bai Anying Xiong Xiang He Xiaolan Li Qin Ran Lei Zhang Manling Jiang Junyi Wang Elaine Lai-Han Leung Pingchang Yang Guoping Li |
| author_facet | Dan Peng Juan Li Yin Li Lingling Bai Anying Xiong Xiang He Xiaolan Li Qin Ran Lei Zhang Manling Jiang Junyi Wang Elaine Lai-Han Leung Pingchang Yang Guoping Li |
| author_sort | Dan Peng |
| collection | DOAJ |
| description | Fibrotic hypersensitivity pneumonitis (FHP) is a fatal interstitial pulmonary disease with limited treatment options. Lung macrophages are a heterogeneous cell population that exhibit distinct subsets with divergent functions, playing pivotal roles in the progression of pulmonary fibrosis. However, the specific macrophage subpopulations and underlying mechanisms involved in the disease remain largely unexplored. In this study, a decision tree model showed that matrix metalloproteinase-14 (MMP14) had higher scores for important features in the up-regulated genes in macrophages from mice exposed to the Saccharopolyspora rectivirgula antigen (SR-Ag). Using single-cell RNA sequencing (scRNA-seq) analysis of hypersensitivity pneumonitis (HP) mice profiles, we identified MMP14high macrophage subcluster with a predominant M2 phenotype that exhibited higher activity in promoting fibroblast-to myofibroblast transition (FMT). We demonstrated that suppressing toll-like receptor 2 (TLR2) and nuclear factor kappa-B (NF-κB) could attenuate MMP14 expression and exosome secretion in macrophages stimulation with SR-Ag. The exosomes derived from MMP14-overexpressing macrophages were found to be more effective in regulating the transition of fibroblasts through exosomal MMP14. Importantly, it was observed that the transfer of MMP14-overexpressing macrophages into mice promoted lung inflammation and fibrosis induced by SR-Ag. NSC-405020 binding to the hemopexin domain (PEX) of MMP-14 ameliorated lung inflammation and fibrosis induced by SR-Ag in mice. Thus, MMP14-overexpressing macrophages may be an important mechanism contributing to the exacerbation of allergic reactions. Our results indicated that MMP14 in macrophages has the potential to be a therapeutic target for HP. |
| first_indexed | 2024-03-08T05:14:11Z |
| format | Article |
| id | doaj.art-7768b464e5c54cda910ed841daae94fa |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-08T05:14:11Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-7768b464e5c54cda910ed841daae94fa2024-02-07T04:42:23ZengElsevierPharmacological Research1096-11862024-02-01200107070MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitisDan Peng0Juan Li1Yin Li2Lingling Bai3Anying Xiong4Xiang He5Xiaolan Li6Qin Ran7Lei Zhang8Manling Jiang9Junyi Wang10Elaine Lai-Han Leung11Pingchang Yang12Guoping Li13Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China; Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaDepartment of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaLaboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, ChinaCancer Center, Faculty of Health Sciences, University of Macau, Macau; MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau; Corresponding author at: Cancer Center, Faculty of Health Sciences, University of Macau, Macau.Institute of Allergy & Immunology, Shenzhen University School of Medicine, State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University, Shenzhen 518060, China; Corresponding author.Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, China; Corresponding author at: Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China.Fibrotic hypersensitivity pneumonitis (FHP) is a fatal interstitial pulmonary disease with limited treatment options. Lung macrophages are a heterogeneous cell population that exhibit distinct subsets with divergent functions, playing pivotal roles in the progression of pulmonary fibrosis. However, the specific macrophage subpopulations and underlying mechanisms involved in the disease remain largely unexplored. In this study, a decision tree model showed that matrix metalloproteinase-14 (MMP14) had higher scores for important features in the up-regulated genes in macrophages from mice exposed to the Saccharopolyspora rectivirgula antigen (SR-Ag). Using single-cell RNA sequencing (scRNA-seq) analysis of hypersensitivity pneumonitis (HP) mice profiles, we identified MMP14high macrophage subcluster with a predominant M2 phenotype that exhibited higher activity in promoting fibroblast-to myofibroblast transition (FMT). We demonstrated that suppressing toll-like receptor 2 (TLR2) and nuclear factor kappa-B (NF-κB) could attenuate MMP14 expression and exosome secretion in macrophages stimulation with SR-Ag. The exosomes derived from MMP14-overexpressing macrophages were found to be more effective in regulating the transition of fibroblasts through exosomal MMP14. Importantly, it was observed that the transfer of MMP14-overexpressing macrophages into mice promoted lung inflammation and fibrosis induced by SR-Ag. NSC-405020 binding to the hemopexin domain (PEX) of MMP-14 ameliorated lung inflammation and fibrosis induced by SR-Ag in mice. Thus, MMP14-overexpressing macrophages may be an important mechanism contributing to the exacerbation of allergic reactions. Our results indicated that MMP14 in macrophages has the potential to be a therapeutic target for HP.http://www.sciencedirect.com/science/article/pii/S1043661824000148Hypersensitivity pneumonitisMMP14MacrophageExosomeFibroblast-to-myofibroblast transitionPulmonary fibrosis |
| spellingShingle | Dan Peng Juan Li Yin Li Lingling Bai Anying Xiong Xiang He Xiaolan Li Qin Ran Lei Zhang Manling Jiang Junyi Wang Elaine Lai-Han Leung Pingchang Yang Guoping Li MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis Pharmacological Research Hypersensitivity pneumonitis MMP14 Macrophage Exosome Fibroblast-to-myofibroblast transition Pulmonary fibrosis |
| title | MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis |
| title_full | MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis |
| title_fullStr | MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis |
| title_full_unstemmed | MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis |
| title_short | MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis |
| title_sort | mmp14high macrophages orchestrate progressive pulmonary fibrosis in sr ag induced hypersensitivity pneumonitis |
| topic | Hypersensitivity pneumonitis MMP14 Macrophage Exosome Fibroblast-to-myofibroblast transition Pulmonary fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824000148 |
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