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Pseudomonas aeruginosa Induced Lung Injury Model
Published on: October 29, 2014
Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung
Emily M King1, Yifan Zhao2, Camille M Moore2
1Medical Scientist Training Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
Abstract:
Macrophages are required for healthy repair of the lungs following injury, but they are also implicated in driving dysregulated repair with fibrosis. How these 2 distinct outcomes of lung injury are mediated by different macrophage subsets is unknown. To assess this, single-cell RNA-Seq was performed on lung macrophages isolated from mice treated with LPS or bleomycin. Macrophages were categorized based on anatomic location (airspace versus interstitium), developmental origin (embryonic versus recruited monocyte derived), time after inflammatory challenge, and injury model. Analysis of the integrated dataset revealed that macrophage subset clustering was driven by macrophage origin and tissue compartment rather than injury model. Gpnmb-expressing recruited macrophages that were enriched for genes typically associated with fibrosis were present in both injury models. Analogous GPNMB-expressing macrophages were identified in datasets from both fibrotic and nonfibrotic lung disease in humans. We conclude that this subset represents a conserved response to tissue injury and is not sufficient to drive fibrosis. Beyond this conserved response, we identified that recruited macrophages failed to gain resident-like programming during fibrotic repair. Overall, fibrotic versus nonfibrotic tissue repair is dictated by dynamic shifts in macrophage subset programming and persistence of recruited macrophages.
Insights
Lung macrophages play a dual role in repair. This study identifies specific macrophage subsets and their origins that dictate whether lung repair is healthy or leads to fibrosis.
Area of Science:
- Immunology
- Pulmonary Medicine
- Cell Biology
Background:
- Macrophages are crucial for lung repair after injury.
- However, they can also drive fibrotic lung disease.
- The specific macrophage subsets mediating these distinct outcomes remain unclear.
Purpose of the Study:
- To investigate the distinct macrophage subsets involved in lung repair following injury.
- To determine how macrophage origin and location influence lung repair outcomes (healthy vs. fibrotic).
Main Methods:
- Single-cell RNA sequencing (scRNA-Seq) of lung macrophages from mice after LPS or bleomycin injury.
- Categorization of macrophages based on location, origin, time, and injury model.
- Integrated dataset analysis to identify macrophage subset clustering drivers.
Main Results:
- Macrophage clustering was primarily driven by origin and tissue compartment, not the injury model.
- GPNMB-expressing recruited macrophages, associated with fibrosis genes, were found in both injury models and human lung disease.
- These GPNMB-expressing macrophages represent a conserved response to injury but are insufficient to cause fibrosis.
- Recruited macrophages failed to adopt resident-like programming during fibrotic repair.
Conclusions:
- Fibrotic versus non-fibrotic lung repair is determined by dynamic programming shifts in macrophage subsets.
- The persistence of recruited macrophages is a key factor in fibrotic repair.
- A conserved macrophage response to injury exists, but fibrotic outcomes depend on specific programming and persistence dynamics.
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