Journal Article

NR4A1 deletion promotes pro-angiogenic polarization of macrophages derived from classical monocytes in a mouse model of neovascular age-related macular degeneration

Cuda, Carla M., Droho, Steven, Lavine, Jeremy A., Sterling, Jacob K., Rajesh, Amrita, Chan, Kyle S., Voigt, Andrew P., Perlman, Harris

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Ablation / Age / Analysis / Angiogenesis / Animal models / Animals / Antibodies / B cells / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Care and treatment / CD11c antigen / Cell activation / Cell growth / Choroidal neovascularization / Choroidal Neovascularization - genetics / Chromosome deletion / CX3CR1 protein / Development and progression / Diabetes / Diabetic retinopathy / Disease Models, Animal / Experiments / Flow cytometry / Genomes / Genomics / Health aspects / Immunology / Lasers / Macrophage / Macrophages / Macrophages - physiology / Macular degeneration / Macular Degeneration - genetics / Mice / Mice, Inbred C57BL / Microglia / Monocyte / Monocytes / Neovascular age-related macular degeneration / Neovascularization / Neurobiology / Neuroinflammation in the Retina / Neurology / Neurosciences / Non-classical monocytes / Patient outcomes / Physiological aspects / Software / Transcriptomics / Vascular endothelial growth factor / Vascularization