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

作者全名："Peng, Dan; Li, Juan; Li, Yin; Bai, Lingling; Xiong, Anying; He, Xiang; Li, Xiaolan; Ran, Qin; Zhang, Lei; Jiang, Manling; Wang, Junyi; Leung, Elaine Lai -Han; Yang, Pingchang; Li, Guoping"

作者地址："[Peng, Dan] Shenzhen Univ, Sch Biomed Engn, Med Sch, Natl Reg Key Technol Engn Lab Med Ultrasound,Guang, Shenzhen 518060, Peoples R China; [Peng, Dan; Li, Juan; Bai, Lingling; Xiong, Anying; He, Xiang; Li, Xiaolan; Ran, Qin; Zhang, Lei; Jiang, Manling; Wang, Junyi; Li, Guoping] Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Inst Resp Hlth, Lab Allergy & Precis Med,Affiliated Hosp, Chengdu 610000, Peoples R China; [Peng, Dan; Li, Juan; Bai, Lingling; Xiong, Anying; He, Xiang; Li, Xiaolan; Ran, Qin; Zhang, Lei; Jiang, Manling; Wang, Junyi; Li, Guoping] ChongQing Med Univ, Chengdu Peoples Hosp Branch 3, Dept Pulm & Crit Care Med, Natl Clin Res Ctr Resp Dis,Affiliated Hosp, Chengdu 610000, Peoples R China; [Li, Yin] Fudan Univ, Dept Thorac Surg, Zhongshan Hosp, Shanghai 200032, Peoples R China; [Leung, Elaine Lai -Han] Univ Macau, Fac Hlth Sci, Canc Ctr, Macau, Peoples R China; [Leung, Elaine Lai -Han] Univ Macau, MOE Frontiers Sci Ctr Precis Oncol, Macau, Peoples R China; [Yang, Pingchang] Shenzhen Univ, Inst Allergy & Immunol, Sch Med, State Key Lab Resp Dis Allergy Div, Shenzhen, Peoples R China"

通信作者："Li, GP (通讯作者)，Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Inst Resp Hlth, Lab Allergy & Precis Med,Affiliated Hosp, Chengdu 610000, Peoples R China.; Leung, ELH (通讯作者)，Univ Macau, Fac Hlth Sci, Canc Ctr, Macau, Peoples R China.; Yang, PC (通讯作者)，Shenzhen Univ, Inst Allergy & Immunol, Sch Med, State Key Lab Resp Dis Allergy Div, Shenzhen, Peoples R China."

来源：PHARMACOLOGICAL RESEARCH

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001170646500001

JCR分区：Q1

影响因子：9.3

年份：2024

卷号：200

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Hypersensitivity pneumonitis; MMP14; Macrophage; Exosome; Fibroblast-to-myofibroblast transition; Pulmonary fibrosis

摘要："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 (SRAg). 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-kappa B) 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."

基金机构：Health Commission of Chengdu [2020-YF05-00003-SN]; [2023269]; [2023134]; [2021011]; [2021040]; [CSY-YN-01-2023-024]; [CSY-YN-01-2023-048]

基金资助正文："This work was supported by the National Natural Science Foundation of China (82370022, 82370023, 82300088, 82200079), National Health Commission of the People's Republic of China (51010023T000009208830), Natural Science Foundation of Sichuan Province (23NSFSC1736), Sichuan Medical Association (Q20009), Chengdu High-level Key Clinical Specialty Construction Project (ZX20201202020), Chengdu Science and Technology Bureau (2021-YF09-00107-SN, 2020-YF05-00003-SN) , Health Commission of Chengdu (2023269, 2023134, 2021011, 2021040) and The Third People's Hospital of Chengdu (CSY-YN-01-2023-024, CSY-YN-01-2023-048) .r YF09-00107-SN, 2020-YF05-00003-SN) , Health Commission of Chengdu (2023269, 2023134, 2021011, 2021040) and The Third Peo-ple's Hospital of Chengdu (CSY-YN-01-2023-024, CSY-YN-01-2023-048) ."