Extracellular matrix anchored neutrophils drive pulmonary fibrosis in mice

Pulmonary fibrosis (PF) is a progressive lung disease characterized by chronic immune dysregulation and excessive extracellular matrix (ECM) remodeling. Neutrophils, traditionally linked to acute inflammation, are increasingly recognized for their role in fibrosis. In this study, we identified a unique subset of neutrophils undergoing reverse transendothelial migration (rTEM) in the lungs of a silicosis mouse model induced by intratracheal SiO₂ instillation. Using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and ECM proteomics, we found that rTEM neutrophils were retained in fibrotic regions via ICAM1-mediated interactions with the ECM. Mechanistically, macrophage-derived cathepsin C (CTSC), accumulating in the ECM, cleaved ICAM1 into its soluble form (sICAM1), which promoted fibroblast activation and exacerbated fibrosis. In vivo depletion of neutrophils or macrophages reduced ICAM1 and CTSC levels, alleviating fibrosis and underscoring their pathogenic roles. These findings establish a direct link between ECM, rTEM neutrophils, and fibrosis, highlighting CTSC and ICAM1 as promising therapeutic targets. All animal experiments were performed using male mice.

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Publication Details

Journal
Nature Communications
Published
2025-11-26
DOI
https://doi.org/10.1038/s41467-025-66633-8
Citations
2
Primary Topic
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Type
article
Field-Weighted Citation Impact
1.59
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article

Extracellular matrix anchored neutrophils drive pulmonary fibrosis in mice

Shuangfeng Zi, Shencun Fang, Bin Zhu, Ka Lou Yu et al.
2 citations
Nature Communications
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
1.59
article

Extracellular matrix anchored neutrophils drive pulmonary fibrosis in mice

Shuangfeng Zi, Shencun Fang, Bin Zhu, Ka Lou Yu, Jie Huang, Yi Rong, Jie Chao, Jing Wang, Chi Liu, Wei Luo, Wei Zhang, Jianmei Ma, Mengjie Xu, Hanbin Chen, Xinxin Zhang, Liliang Yang, Piaopiao Sun, Ruiqing Mao
article en
2 citations

Abstract

Pulmonary fibrosis (PF) is a progressive lung disease characterized by chronic immune dysregulation and excessive extracellular matrix (ECM) remodeling. Neutrophils, traditionally linked to acute inflammation, are increasingly recognized for their role in fibrosis. In this study, we identified a unique subset of neutrophils undergoing reverse transendothelial migration (rTEM) in the lungs of a silicosis mouse model induced by intratracheal SiO₂ instillation. Using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and ECM proteomics, we found that rTEM neutrophils were retained in fibrotic regions via ICAM1-mediated interactions with the ECM. Mechanistically, macrophage-derived cathepsin C (CTSC), accumulating in the ECM, cleaved ICAM1 into its soluble form (sICAM1), which promoted fibroblast activation and exacerbated fibrosis. In vivo depletion of neutrophils or macrophages reduced ICAM1 and CTSC levels, alleviating fibrosis and underscoring their pathogenic roles. These findings establish a direct link between ECM, rTEM neutrophils, and fibrosis, highlighting CTSC and ICAM1 as promising therapeutic targets. All animal experiments were performed using male mice.

Nature CommunicationsVol. 16(1)
Central South University (CN), Xizang Minzu University (CN), Bengbu Medical College (CN), Dalian Medical University (CN), Zhongda Hospital Southeast University (CN), Nanjing Brain Hospital (CN), Nanjing Chest Hospital (CN), Southeast University (CN), Nanjing Medical University (CN)
Openalex Percentile: Top 14%
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
1.59
DOIOpen Access PDFOpenAlex
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