Work

Extracellular matrix anchored neutrophils drive pulmonary fibrosis in mice

Year: 2025

Type: article

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. Pulmonary fibrosis involves chronic inflammation and extracellular matrix remodeling but the contribution of neutrophils is unclear. Here the authors show that reverse-migrating neutrophils anchored in the lung extracellular matrix exacerbate fibrosis via ICAM1 and macrophage derived cathepsin C.

Source: Nature Communications

DOI: 10.1038/s41467-025-66633-8