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Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade [Ipt]

ABSTRACT: Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Recently, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2 has been described in several models of organ injury and cancer, and linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Unexpectedly, using a bleomycin and COVID19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not by themselves drivers of fibrosis in the lung.

ORGANISM(S): Mus musculus

PROVIDER: GSE277297 | GEO | 2024/09/16

REPOSITORIES: GEO

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Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade

Project description:Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Recently, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2 has been described in several models of organ injury and cancer, and linked to fibrosis in mice and humans. Here, we show that Notch2 blockade given systemically or locally led to an increase in this putative pro-fibrotic macrophage in the lung. Single cell RNA sequencing suggested that the newly arising population derived from monocytes when Notch2 blockade was systemic or derived from alveolar macrophages when Notch2 blockade was local. Unexpectedly, using a bleomycin and COVID19 model of lung injury and fibrosis, we found that the expansion of these macrophages before lung injury ameliorated rather than promoted fibrosis. This suggests that these damage-associated macrophages are not drivers of fibrosis in the lung.

2024-09-14 | GSE243289 | GEO

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2017-06-25 | GSE82158 | GEO

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

Project description: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.

2024-12-01 | GSE280003 | GEO

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2023-10-08 | PXD035269 | Pride

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2024-09-30 | GSE269733 | GEO

Cell origin dictates programming of resident versus recruited macrophages during acute lung injury

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2024-04-14 | GSE263544 | GEO

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