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NR4A1 deletion promotes pro-angiogenic polarization of macrophages derived from classical monocytes in a mouse model of neovascular age-related macular degeneration
BACKGROUND: Neovascular age-related macular degeneration causes vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Cx3cr1(−/−) mice display alterations in non-classical monocytes and microglia with increased CNV size, suggesting that non-classical monocytes may inh...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10588116/ https://www.ncbi.nlm.nih.gov/pubmed/37858232 http://dx.doi.org/10.1186/s12974-023-02928-1 |
Sumario: | BACKGROUND: Neovascular age-related macular degeneration causes vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Cx3cr1(−/−) mice display alterations in non-classical monocytes and microglia with increased CNV size, suggesting that non-classical monocytes may inhibit CNV formation. NR4A1 is a transcription factor that is necessary for maturation of non-classical monocytes from classical monocytes. While Nr4a1(−/−) mice are deficient in non-classical monocytes, results are confounded by macrophage hyper-activation. Nr4a1(se2/se2) mice lack a transcriptional activator, resulting in non-classical monocyte loss without macrophage hyper-activation. MAIN BODY: We subjected Nr4a1(−/−) and Nr4a1(se2/se2) mice to the laser-induced CNV model and performed multi-parameter flow cytometry. We found that both models lack non-classical monocytes, but only Nr4a1(−/−) mice displayed increased CNV area. Additionally, CD11c(+) macrophages were increased in Nr4a1(−/−) mice. Single-cell transcriptomic analysis uncovered that CD11c(+) macrophages were enriched from Nr4a1(−/−) mice and expressed a pro-angiogenic transcriptomic profile that was disparate from prior reports of macrophage hyper-activation. CONCLUSIONS: These results suggest that non-classical monocytes are dispensable during CNV, and NR4A1 deficiency results in increased recruitment of pro-angiogenic macrophages. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02928-1. |
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