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 1

CX3CR1 expression in AMD.

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CX3CR1 expression in AMD. (A) CX3CR1 (fast red labeling) was expressed i...
(A) CX3CR1 (fast red labeling) was expressed in the inner retina (arrows); no CX3CR1-positive cells were found in the outer nuclear layer (ONL), photoreceptor OSs, or RPE. Inset: Confocal images of the nerve fiber layer of double-labeled retinal flatmounts showed the ramified morphology of cells expressing CX3CR1 (green) and their close proximity to the retinal vasculature (Ulex red) in a healthy eye. (B) In affected zones of the macula of age-matched subjects with AMD, additional CX3CR1-positive cells (arrows) were found in and below the outer nuclear layer that contains the photoreceptors. Inset: These cells were large and bloated (green, CX3CR1; blue, DAPI). (C–E) CX3CR1-expressing cells (C) were ramified cells that also labeled positive for the MC marker CD18 (red, D); merged image is shown in E. (F) Drusen contained acellular CX3CR1 deposits (arrows). (G) CX3CR1-positive cells were in close physical contact with CNV (arrows). Results are representative for immunohistochemistry from 4 eyes with AMD and 3 age-matched control eyes. INL, inner nuclear layer; IPL, inner plexiform layer. Scale bar: 50 μm (A–G and A, inset); 20 μm (B, inset).