CD163 macrophages drive rapid pulmonary fibrosis via osteopontin secretion.

BACKGROUND

Rapid pulmonary fibrosis (RPF) is a severe condition characterized by the rapid accumulation of excessive extracellular matrix (ECM), resulting in high mortality among patients with severe respiratory infections. CD163 macrophages were found to be enriched in RPF patients, their role in this disease requires elucidation.

METHODS

We integrated single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) analyses of COVID-19-associated RPF patients, alongside an LPS three-hit-induced murine RPF model and in vitro co-culture systems. Genetic (CD163 mice) and functional (Osteopontin (OPN) silencing) approaches were employed to dissect the profibrotic role of CD163 macrophages.

RESULTS

scRNA-seq and snRNA-seq analyses identified an enrichment of CD163 macrophages in the lungs of COVID-19 patients with RPF, along with upregulated expression of fibrosis-associated genes, such as SPP1 (encoding OPN). In the murine model, CD163 macrophages promoted RPF progression, with OPN expression positively correlating with collagen deposition. Moreover, silencing OPN impaired the profibrotic activity of CD163 macrophages in vitro.

CONCLUSIONS

CD163 macrophages are enriched in rapid pulmonary fibrosis patients and the mouse model, facilitating disease progression through the secretion of OPN. The CD163 macrophage-OPN axis could be a potential therapeutic target for rapid pulmonary fibrosis.