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<p>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.</p>

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Extracellular matrix anchored neutrophils drive pulmonary fibrosis in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Liliang Yang,
  • Piaopiao Sun,
  • Jing Wang,
  • Mengjie Xu,
  • Binyan Zhu,
  • Keqing Yu,
  • Yi Rong,
  • Ruiqing Mao,
  • Shuangfeng Zi,
  • Chi Liu,
  • Jie Huang,
  • Jianmei Ma,
  • Hanbin Chen,
  • Wei Luo,
  • Wei Zhang,
  • Xinxin Zhang,
  • Shencun Fang,
  • Jie Chao

摘要

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.