CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration
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
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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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 2

The M280 polymorphism leads to CX3CR1 dysfunction and impaired migration.

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The M280 polymorphism leads to CX3CR1 dysfunction and impaired migration...
(A) Representative CCL2-dependent migration through CX3CL1-coated filters of monocytes from individuals homozygous for the 2 extreme haplotypes of CX3CR1 (VT and IM). Flow cytometry was used to count the number of CD14-positive cells that migrated into the lower chamber. Each data point is the mean ± SEM of 3 different determinations. (B) Genetic variations of CX3CR1-impaired CCL2-dependent migration through filters coated with CX3CL1. Monocytes from individuals homozygous for CX3CR1-IM variants (n = 5) have less CCL2-dependent chemotactic ability in the presence of a CX3CL1-coated filter than do monocytes from individuals homozygous for CX3CR1-VT variants (n = 8). Migration ability is expressed as the ratio of the chemotactic index (CI) in response to CCL2 of monocytes migrating through a filter with or without a CX3CL1 coating (chemotactic index without CX3CL1 relative to chemotactic index with CX3CL1). ***P = 0.0006.