CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration.
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.
Combadière
Christophe
C
INSERM U543, Laboratoire d'Immunologie Cellulaire, Paris, France.
Feumi
Charles
C
Raoul
William
W
Keller
Nicole
N
Rodéro
Mathieu
M
Pézard
Adeline
A
Lavalette
Sophie
S
Houssier
Marianne
M
Jonet
Laurent
L
Picard
Emilie
E
Debré
Patrice
P
Sirinyan
Mirna
M
Deterre
Philippe
P
Ferroukhi
Tania
T
Cohen
Salomon-Yves
SY
Chauvaud
Dominique
D
Jeanny
Jean-Claude
JC
Chemtob
Sylvain
S
Behar-Cohen
Francine
F
Sennlaub
Florian
F
D000483:Alleles; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000235:genetics; D020256:Choroidal Neovascularization / Q000235:genetics / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008268:Macular Degeneration / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D011110:Polymorphism, Genetic; D019707:Receptors, Chemokine / Q000235:genetics*; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D015593:Retinal Drusen / Q000235:genetics / Q000473:pathology
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D019707:Receptors, Chemokine