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Xavier P. Guillonneau, Constance Auvynet, William Raoul, Serge Camelo, Sophie Lavalette, Olivier Levy, Christophe Combadière, Florian Sennlaub; Contrasting Effects Of The Ccr2/ccl2 And The Cx3cr1/cx3cl1 Axis In Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):979.
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Intraocular CCL2 levels have been shown to be increased in AMD and a CX3CR1 polymorphism is associated with AMD. Senescent CCL2- and CX3CR1-deficient mice were shown to present cardinal features of human age-related macular degeneration (AMD). It was shown that both aged knock-out mice exhibited retinal degeneration and drusen-like deposits. Moreover, in Cx3cr1-/- mice macrophages/microglial cells (Mϕ/MCs) accumulated subretinally with age and in two acute degenerative models, i.e laser impact and light-induced injury models. In light-induced injury and age models, this subretinal accumulation preceded retinal degeneration. In this study, using CCL2-, CX3CR1-, and CCL2/CX3CR1-deficient mice, we compared drusen formation, microglia accumulation and retinal degeneration with age and in a light-induced injury model.
wild type, Ccl2-/-, Cx3cr1-/- and Ccl2-/-Cx3cr1-/- mice were analyzed at 3, 6, 9, 12 and 18 months of age and 3-month-old mice were submitted to a light injury model (4 days of constant 4500 lux). "Drusen" appearance was evaluated by fundoscopy (18 months). Subretinal Mϕ/MCs were quantified on IBA-1 stained flatmounts of the RPE and retina (3, 6, 9, and 12months and d14 after illumination) and retinal degeneration was evaluated on histological sections (18 months and d21 after illumination). CCL2 expression was analyzed by RT-PCR, immunohistochemistry and Elisa.
CCL2 was overexpressed in aged and illuminated Cx3cr1-/- mice and located to the subretinal space. The subretinal Mϕ/MCs accumulation observed in 6, 9 and 12-months-old Cx3cr1-/- mice and d14 illuminated Cx3cr1-/- mice was not observed in Ccl2-/- mice and significantly inhibited in Ccl2-/-Cx3cr1-/- mice. Similarly "drusen" appearance observed in Cx3cr1-/- mice was significantly inhibited in Ccl2-/-Cx3cr1-/- mice. Retinal degeneration observed in 18-month-old and light-exposed Cx3cr1-/- mice but not in Ccl2-/-mice, was significantly inhibited in Ccl2-/-Cx3cr1-/- mice.
CCL2 contributes to subretinal Mϕ/MC accumulation, "drusen" formation and retinal degeneration in Cx3cr1-/- mice.
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