CD163+ macrophages drive rapid pulmonary fibrosis via osteopontin secretion
Wenjun Ding1, Suihui Deng1, Zhiping Wang1
1State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, China; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
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.
Insights
CD163-positive macrophages drive rapid pulmonary fibrosis (RPF) by secreting Osteopontin (OPN). Targeting this CD163-macrophage-OPN pathway may offer new treatments for RPF.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cell Biology
Background:
- Rapid pulmonary fibrosis (RPF) is a fatal condition linked to severe respiratory infections, marked by excessive extracellular matrix accumulation.
- CD163-positive macrophages are found in increased numbers in RPF patients, but their specific role remains unclear.
Purpose of the Study:
- To investigate the role of CD163-positive macrophages in the pathogenesis of COVID-19-associated RPF.
- To explore the potential of the CD163-macrophage-Osteopontin (OPN) axis as a therapeutic target for RPF.
Main Methods:
- Integrated single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) in human RPF samples.
- Utilized a three-hit LPS-induced murine RPF model and in vitro co-culture systems.
- Employed genetic (CD163 knockout) and functional (OPN silencing) approaches.
Main Results:
- CD163-positive macrophages and fibrosis-associated gene SPP1 (encoding OPN) were enriched in COVID-19 RPF lungs.
- In the murine model, CD163-positive macrophages exacerbated RPF, with OPN levels correlating with collagen deposition.
- In vitro, OPN silencing reduced the profibrotic activity of CD163-positive macrophages.
Conclusions:
- CD163-positive macrophages promote RPF progression via Osteopontin (OPN) secretion.
- The CD163-macrophage-OPN interaction represents a promising therapeutic target for RPF.
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