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 3

SrMCs accumulate in CX3CR1–/– C57BL/6 mice with age and lead to retinal degeneration.

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SrMCs accumulate in CX3CR1–/– C57BL/6 mice with age and lead to retinal ...
(A) Sections from an 18-month-old CX3CR1+/GFP mouse showed GFP-positive cells in close proximity to Griffonia simplicifolia–positive (red) retinal endothelial cells. (B) Sections from an 18-month-old CX3CR1GFP/GFP mouse revealed the same distribution of GFP-positive cells in the inner retina but showed additional subretinal GFP-positive cells juxtaposed to the RPE cell layer (arrows). (C and D) Confocal images of the outer plexiform layer revealed that the entire network of ramified MCs was GFP positive and similarly dense in CX3CR1+/GFP (C) and CX3CR1GFP/GFP mice (D). (E and F) RPE flatmounts of aged mice showed a strong accumulation of SrMCs in CX3CR1+/GFP (E) and CX3CR1GFP/GFP mice (F). (G) Quantification of subretinal GFP-positive cells on RPE flatmounts revealed that SrMCs accumulated progressively in CX3CR1GFP/GFP mice and were significantly more numerous than in CX3CR1+/GFP mice at all time points. (H and I) Toluidine blue–stained epoxy retinal semithin sections showed degeneration of photoreceptors in 18-month-old CX3CR1–/– (I) mice compared with CX3CR1+/+ (H) mice. (J) Measurements of photoreceptor cell layer thickness showed significant thinning of the photoreceptor cell layer in CX3CR1–/– mice compared with CX3CR1+/+ mice. Experiments were performed on 4–8 eyes from different mice per group. *P < 0.05. Ch, choroid. ROS, rod OS. Scale bars: 50 μm.