Author:
Droho Steven,Voigt Andrew P.,Sterling Jacob K.,Rajesh Amrita,Chan Kyle S.,Cuda Carla M.,Perlman Harris,Lavine Jeremy A.
Abstract
Abstract
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. Nr4a1se2/se2 mice lack a transcriptional activator, resulting in non-classical monocyte loss without macrophage hyper-activation.
Main body
We subjected Nr4a1−/− and Nr4a1se2/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.
Funder
Illinois Society for the Prevention of Blindness
Rheumatology Research Foundation
National Institute of Allergy and Infectious Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Aging
National Cancer Institute
Northwestern University
Research to Prevent Blindness
National Eye Institute
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology,Immunology,General Neuroscience