MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis

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

Pharmacological Research (Feb 2024)

MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis

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

Affiliations

Dan Peng: Guangdong 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, China
Juan Li: 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
Yin Li: Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Lingling Bai: 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
Anying Xiong: 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
Xiang He: 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
Xiaolan Li: 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
Qin Ran: 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
Lei Zhang: 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
Manling Jiang: 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
Junyi Wang: 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
Elaine Lai-Han Leung: Cancer 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.
Pingchang Yang: 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.
Guoping Li: 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.

Journal volume & issue: Vol. 200
p. 107070

Abstract

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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.

Published in Pharmacological Research

ISSN: 1096-1186 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.sciencedirect.com/journal/pharmacological-research

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