Recently, the research team led by Professors Chao Jie and Qiu Haibo from the Jiangsu Province Key Laboratory of Critical Care Medicine, SEU, made significant strides in the study of pulmonary fibrosis. Their findings, titled “Extracellular matrix anchored neutrophils drive pulmonary fibrosis in mice,” was published inNature Communications, a prestigious international journal.

This study systematically reveals that a special subset of “reverse transendothelial migration neutrophils” (rTEM neutrophils) are anchored in fibrotic lesions by the extracellular matrix (ECM) during the progression of pulmonary fibrosis. Through synergistic action with key protease cathepsin C (CTSC) secreted by macrophages, these neutrophils drive the continuous exacerbation of fibrosis. This finding provides a new theoretical foundation and potentialintervention strategy for the clinical prevention and treatment of pulmonary fibrosis.

Pulmonary fibrosis is a fatal lung disease caused by chronic inflammation and abnormal matrix remodelling. Currently, there are no effective treatments to reverse the disease. Traditional views suggest that neutrophils primarily participate in acute inflammatory responses, with limited roles during the chronic fibrosis phase.

This study established a silica (SiO?)-induced mouse model. The study found that a large number of rTEM neutrophils, characterised by high ICAM1 and low CXCR1 expression, were retained in fibrotic regions of the lung, suggesting that they may still play a pathogenic role in the later stages of the disease.

The research team, combining single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and ECM proteomics, for the first time discovered that rTEM neutrophils predominantly aggregate in inflammatory and fibrotic regions. These neutrophils interact with the ECM via ICAM1-integrin signals and are “anchored” in the lung tissue. The experiments demonstrated that these rTEM neutrophils could directly promote the activation, proliferation, and collagen deposition of fibroblasts, thereby accelerating the progression of fibrosis. The study further revealed that cathepsin C (CTSC), released by macrophages, accumulated in the ECM, where it cleaves ICAM1 to generate soluble sICAM1. This soluble form of ICAM1 could then activate fibroblasts and promote collagen synthesis. In CTSC knockout mice, ICAM1 cleavage was reduced, and the severity of pulmonary fibrosis was significantly alleviated. Furthermore, the depletion of neutrophils in vivo reduced ICAM1 levels and alleviated fibrosis, confirming the critical role of the CTSC-ICAM1 pathway in disease progression.

SEU is the primary affiliation of this paper. Ph.D. student Yang Liliang, postgraduate student Sun Piaopiao, and young faculty member Wang Jing are co-first authors of the paper, with Professors Chao Jie and Fang Shencun from Nanjing Chest Hospital being co-corresponding authors. Dr. Zi Shuangfeng from Prof. Qiu Haibo's team, along with undergraduate students Yu Keqing, Xu Mengjie, Zhu Binyan, and other members of SEU's Student Research Training Program (SRTP), contributed to the research. The study was supported by the Jiangsu Provincial Basic Research Program—Key Projects, the National Natural Science Foundation, the National Key Research and Development Program of China, the Jiangsu Provincial Science and Technology Program “Frontier Technology Research and Development Projects,” as well as technical support from SEU's Big Data Computing Center.

Paper's link: https://www.nature.com/articles/s41467-025-66633-8

Contributed by: School of Medicine, SEU

Translated by: Melody Zhang

Proofread by: Gao Min

Edited by: Li Xinchang