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 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.
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