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 5

Drusen observed in CX3CR1 knockout animals are bloated SrMCs.

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Drusen observed in CX3CR1 knockout animals are bloated SrMCs. (A–D) Comp...
(A–D) Comparison of fundus photos and micrographs of a RPE flatmount in tangential light of 1-year-old CX3CR1+/+ (A and C) and CX3CR1–/– mice (B and D) revealed multiple drusen in CX3CR1–/– mice. (E–G) Higher-magnification image of a drusen (arrow) in a CX3CR1GFP/GFP mouse in tangential light (E) superimposed with GFP-positive (green; red, Phalloidin; blue, DAPI) subretinal ramified cells (F) on RPE flatmounts. Merge of tangential light and DAPI is shown in G. (H and I) GFP-positive subretinal ramified cells (H) on CX3CR1GFP/GFP RPE flatmounts were positive for the MC marker 5D4 (red, I). (J and K) Histological sections of historesin-embedded 12-month-old CX3CR1+/+ (J) and CX3CR1–/– (K) eyes showed subretinal cells abutting the RPE in CX3CR1–/– (K, arrow) but not in CX3CR1+/+ mice. (L) Electron microscopy of the RPE/OS interface in CX3CR1–/– mice revealed subretinal cells (asterisk) with multiple phagosomes juxtaposed to the RPE cell layer. (M) Higher magnification of these subretinal cells revealed multiple lipid deposits and typical remnants of rod OSs in phagosomes (arrow). (N) Subretinal CD11b-positive (green) dendritic cells contained rhodopsin-positive inclusions (red) in confocal micrographs of RPE flatmounts from CX3CR1–/– mice. Results are representative of at least 3 independent experiments. Scale bars: 500 μm (A–D), 50 μm (E–G), 20 μm (H–K and N), 1 μm (L and M).