Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung.

Macrophages are required for healthy repair of the lungs following injury, but they are also implicated in driving dysregulated repair with fibrosis. How these two distinct outcomes of lung injury are mediated by different macrophage subsets is unknown. To assess this, single-cell RNA sequencing was performed on lung macrophages isolated from mice treated with lipopolysaccharide 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 non-fibrotic 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 non-fibrotic tissue repair is dictated by dynamic shifts in macrophage subset programming and persistence of recruited macrophages.