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Florian Sennlaub, Constance Auvynet, Xavier Guillonneau, Serge Camelo, Sophie Lavalette, Jean-Louis Bourges, Francine Behar-Cohen, William Raoul, Christoph Combadiere; CCL2/CCR2 Chemokine Axis Mediates Inflammatory Monocytes Recruitment To Lesions Of Atrophic Age-related Macular Degeneration And Retinal Degeneration In Cx3cr1 Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1230.
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The chemokine/chemokine receptor axis CCL2/CCR2 has been shown to mediate inflammatory monocyte recruitment in a number of neurodegenerative disorders. Intraocular CCL2 levels are increased in wet AMD. We have shown that subretinal macrophages/microglial cells (Mφ/MCs) accumulation in Cx3cr1-/- mice is associated with photoreceptor degeneration. We here investigated intraocular CCL2 expression and CCR2+ inflammatory monocyte recruitment in Geographic Atrophy (GA) and Cx3cr1-/- mice and their influence on photoreceptor degeneration in Cx3cr1-/- mice.
[CCL2] was measured by ELISA in aqueous humors of 18 GA patients and 22 age-matched control patients with no signs of AMD undergoing cataract surgery. CCL2 expression and the number of CCR2+inflammatory monocytes were analyzed in macular sections of donor tissues with GA lesions (n=8) and age matched control eyes (n=5). CCL2 expression (rt-PCR and ELISA) and inflammatory monocyte infiltration (cytometrie) was analyzed in light-injured Ccl2-/-, Cx3cr1-/- and Ccl2-/-Cx3cr1-/- mice. The influence of inflammatory monocyte infiltration on subretinal Mφ/MC accumulation and photoreceptor degeneration was analyzed using clodronate liposomes and CCR2 inhibitors.
We show that atrophic age-related macular disease (AMD) is associated with increased intraocular CCL2 levels and subretinal CCR2+ "inflammatory" monocyte infiltration. Using the Cx3cr1-/- mouse model of subretinal Mφ/MC accumulation and photoreceptor degeneration, we show that pharmacological inhibition of CCR2, genetic deletion of CCL2, and depletion of circulating monocytes prevents inflammatory monocyte recruitment, MC/Mφ accumulation, and photoreceptor degeneration in vivo. Our data suggests that CCL2/CCR2 inhibition represents a powerful tool for controlling inflammation and neurodegeneration in AMD.
Our data suggests that CCL2/CCR2 inhibition represents a powerful tool for controlling subretinal inflammation and neurodegeneration in AMD.
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