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 4

SrMC accumulation induces retinal degeneration in albino CX3CR1–/– mice.

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SrMC accumulation induces retinal degeneration in albino CX3CR1–/– mice....
(A and B) RPE flatmounts of albino CX3CR1+/+ BALB/c (A) and CX3CR1–/– BALB/c mice (B) showed more numerous CD11b-positive (green) SrMC abutting the RPE (Phalloidin, red) in CX3CR1-deficient animals. (C) Quantification of subretinal CD11b-positive cells on RPE flatmounts revealed a significantly higher density of MCs in CX3CR1–/– mice at 1 and 2 months of age raised in ambient light conditions. CX3CR1–/– BALB/c mice raised in complete darkness showed significantly fewer SrMC than ambient light–raised CX3CR1–/– BALB/c mice. (D–F) Toluidine blue–stained epoxy retinal semithin sections showed complete degeneration of all photoreceptors in albino CX3CR1–/– BALB/c mice (E) at 4 months of age compared with CX3CR1+/+ BALB/c mice (D). This degeneration was prevented in CX3CR1–/– BALB/c mice raised in darkness (F). (G) Measurements of photoreceptor cell layer thickness showed significant and progressive degeneration in albino CX3CR1–/– BALB/c mice, which was completely reversed by raising CX3CR1–/– BALB/c mice in darkness. Experiments were performed on 8–10 eyes from different mice per group. *P < 0.05. Scale bars: 50 μm.