CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration
Christophe Combadière, … , Francine Behar-Cohen, Florian Sennlaub
Christophe Combadière, … , Francine Behar-Cohen, Florian Sennlaub
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2920-2928. https://doi.org/10.1172/JCI31692.
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Research Article

CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration

Abstract

The role of retinal microglial cells (MCs) in age-related macular degeneration (AMD) is unclear. Here we demonstrated that all retinal MCs express CX3C chemokine receptor 1 (CX3CR1) and that homozygosity for the CX3CR1 M280 allele, which is associated with impaired cell migration, increases the risk of AMD. In humans with AMD, MCs accumulated in the subretinal space at sites of retinal degeneration and choroidal neovascularization (CNV). In CX3CR1-deficient mice, MCs accumulated subretinally with age and albino background and after laser impact preceding retinal degeneration. Raising the albino mice in the dark prevented both events. The appearance of lipid-bloated subretinal MCs was drusen-like on funduscopy of senescent mice, and CX3CR1-dependent MC accumulation was associated with an exacerbation of experimental CNV. These results show that CX3CR1-dependent accumulation of subretinal MCs evokes cardinal features of AMD. These findings reveal what we believe to be a novel pathogenic process with important implications for the development of new therapies for AMD.

Authors

Christophe Combadière, Charles Feumi, William Raoul, Nicole Keller, Mathieu Rodéro, Adeline Pézard, Sophie Lavalette, Marianne Houssier, Laurent Jonet, Emilie Picard, Patrice Debré, Mirna Sirinyan, Philippe Deterre, Tania Ferroukhi, Salomon-Yves Cohen, Dominique Chauvaud, Jean-Claude Jeanny, Sylvain Chemtob, Francine Behar-Cohen, Florian Sennlaub

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Figure 6

SrMCs accumulate after laser injury, exacerbate neovascularization, and induce adjacent retinal degeneration.

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SrMCs accumulate after laser injury, exacerbate neovascularization, and ...
(A and B) At 3 months of age, CX3CR1+/GFP mice displayed some GFP-positive (green) SrMCs adjacent to the CNV (red, Griffonia simplicifolia) 14 days after laser injury (A), and CX3CR1GFP/GFP mice showed strong SrMC accumulation (B). (C) CX3CR1+/GFP mice showed a transient increase of SrMCs after laser impact, peaking at day 7; however, SrMCs in CX3CR1GFP/GFP mice were significantly more numerous at that time and continued to accumulate. (D–F) Immunohistochemistry at day 7 revealed VEGF expression (green) in F4/80-positive activated CX3CR1+/+ MCs (red) in the subretinal space. Nuclei were stained with DAPI (blue). (G and H) Micrographs of fluorescein dextran (green) perfused RPE/choroidal flatmounts double labeled with endothelial cell marker Griffonia simplicifolia (red) 14 days after laser impact in CX3CR1+/+ (G) and CX3CR1–/– (H) mice showed representative CNV. (I) Quantification showed exacerbated neovascularization in the knockout strains. (J) Eyes of CX3CR1+/+ mice (12 months old) showed a normal photoreceptor cell layer 200 μm adjacent to the impact 21 days after laser treatment. (K) At this stage CX3CR1–/– mice displayed SrMCs and a thinned and irregular photoreceptor cell layer. (L) Laser-dependent retinal degeneration (calculated as described in Methods) was significantly more pronounced in CX3CR1–/– mice only at 100 and 200 μm. Experiments were performed on 8–10 eyes from different mice per group. *P < 0.05. Scale bars: 50 μm (A, B, G, H, J, and K), 10 μm (D–F).