MMP14high macrophages orchestrate progressive pulmonary fibrosis in SR-Ag-induced hypersensitivity pneumonitis
1Guangdong 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.
Abstract:
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.
Insights
Matrix metalloproteinase-14 (MMP14)-high macrophages drive fibrotic hypersensitivity pneumonitis (HP) by promoting fibroblast transition. Inhibiting MMP14 or its downstream effects may offer new therapeutic strategies for this severe lung disease.
Area of Science:
- Immunology
- Pulmonary Medicine
- Cell Biology
Background:
- Fibrotic hypersensitivity pneumonitis (FHP) is a severe lung disease with few treatments.
- Lung macrophages are key players in pulmonary fibrosis, but specific roles in FHP are unclear.
Purpose of the Study:
- To investigate the role of macrophage subpopulations and matrix metalloproteinase-14 (MMP14) in the pathogenesis of fibrotic hypersensitivity pneumonitis (FHP).
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) identified MMP14-high macrophages in HP mouse models.
- Investigated MMP14 expression, exosome secretion, and fibroblast-to-myofibroblast transition (FMT) in response to Saccharopolyspora rectivirgula antigen (SR-Ag).
- Evaluated the therapeutic potential of an MMP14 inhibitor (NSC-405020) in vivo.
Main Results:
- MMP14-high macrophages, predominantly M2 phenotype, were identified and linked to increased FMT.
- Suppression of toll-like receptor 2 (TLR2) and nuclear factor kappa-B (NF-κB) pathways reduced MMP14 expression and exosome secretion.
- Exosomes from MMP14-overexpressing macrophages enhanced FMT, and macrophage transfer exacerbated lung fibrosis.
- NSC-405020 treatment ameliorated SR-Ag-induced lung inflammation and fibrosis.
Conclusions:
- MMP14-expressing macrophages contribute significantly to allergic lung inflammation and fibrosis in HP.
- Targeting MMP14 in macrophages presents a promising therapeutic strategy for FHP.
