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

被引：10

作者：

Droho, Steven ^{[1
]}

Voigt, Andrew P. ^{[1
]}

Sterling, Jacob K. ^{[1
]}

Rajesh, Amrita ^{[1
]}

Chan, Kyle S. ^{[1
]}

Cuda, Carla M. ^{[2
]}

Perlman, Harris ^{[2
]}

Lavine, Jeremy A. ^{[1
]}

机构：

[1] Northwestern Univ, Dept Ophthalmol, Feinberg Sch Med, Chicago, IL 60611 USA

[2] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Rheumatol, Chicago, IL 60611 USA

来源：

JOURNAL OF NEUROINFLAMMATION | 2023年 / 20卷 / 01期

关键词：

Angiogenesis; Choroidal neovascularization; Macrophage; Monocyte; Non-classical monocytes; Neovascular age-related macular degeneration; FACTOR-H POLYMORPHISM; RANIBIZUMAB; INFLAMMATION; CXCR4; RISK;

D O I：

10.1186/s12974-023-02928-1

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

BackgroundNeovascular 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 bodyWe 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.ConclusionsThese results suggest that non-classical monocytes are dispensable during CNV, and NR4A1 deficiency results in increased recruitment of pro-angiogenic macrophages.

引用

页数：16