CD163+ macrophages drive rapid pulmonary fibrosis via osteopontin secretion

Abstract

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.

Keywords: CD163(+) macrophages; Osteopontin; Rapid pulmonary fibrosis.