Abstract
Previous studies have shown that CCL2/CX3CR1 deficient mice on C57BL/6N background (with rd8 mutation) have an early onset (6 weeks) of spontaneous retinal degeneration. In this study, we generated CCL2−/−CX3CR1GFP/GFP mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2−/−CX3CR1GFP/GFP mice younger than 6 months. Patches of whitish/yellowish fundus lesions were observed in 17∼60% of 12-month, and 30∼100% of 18-month CCL2−/−CX3CR1GFP/GFP mice. Fluorescein angiography revealed no choroidal neovascularisation in these mice. Patches of retinal pigment epithelium (RPE) and photoreceptor damage were detected in 30% and 50% of 12- and 18-month CCL2−/−CX3CR1GFP/GFP mice respectively, but not in wild-type mice. All CCL2−/−CX3CR1GFP/GFP mice exposed to extra-light (∼800lux, 6 h/day, 6 months) developed patches of retinal atrophy, and only 20–25% of WT mice which underwent the same light treatment developed atrophic lesions. In addition, synaptophysin expression was detected in the outer nucler layer (ONL) of area related to photoreceptor loss in CCL2−/−CX3CR1GFP/GFP mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL2−/−CX3CR1GFP/GFP mice. GABA expression was reduced in the inner retina of aged CCL2−/−CX3CR1GFP/GFP mice. Significantly increased Müller glial and microglial activation was observed in CCL2−/−CX3CR1GFP/GFP mice compared to age-matched WT mice. Macrophages from CCL2−/−CX3CR1GFP/GFP mice were less phagocytic, but expressed higher levels of iNOS, IL-1β, IL-12 and TNF-α under hypoxia conditions. Our results suggest that the deletions of CCL2 and CX3CR1 predispose mice to age- and light-mediated retinal damage. The CCL2/CX3CR1 deficient mouse may thus serve as a model for age-related atrophic degeneration of the RPE, including the dry type of macular degeneration, geographic atrophy.
Highlights
Age-related macular degeneration (AMD) is a disease, in which the neuronal retina of the macula gradually degenerates with age resulting in the loss of central vision [1]
In 2007, Tuo et al reported that the combined deletion of chemokine Ccl2 and Fractalkine receptor Cx3cr1 on C57BL/6N genetic background (i.e., CCL22/2CX3CR12/2 mice) resulted in an early onset of spontaneous retinal degeneration with AMD-like features such as retinal pigment epithelium (RPE) alteration, photoreceptor damage and A2E elevation [30], and the mouse has been considered as a valuable model of AMD [46]
A recent study has shown that the C57BL/ 6N mice have Crb-1 rd8 mutation [31], and it has been suggested that retinal lesions in the Ccl22/2Cx3cr12/2 mice may be caused by rd8 mutation rather than Ccl2 and Cx3cr1 deletion [31,32]
Summary
Age-related macular degeneration (AMD) is a disease, in which the neuronal retina of the macula gradually degenerates with age resulting in the loss of central vision [1]. The disease presents with the accumulation of drusen, yellowish deposits in the macula between the retinal pigment epithelium (RPE) and Bruch’s membrane [1], or reticular pseudo-drusen at the subretinal space [2,3]. The disease may progress to two advanced forms, geographic atrophy (dry AMD) where gradual vision loss occurs due to RPE and photoreceptor cell death, and neovascular AMD (wet AMD) where visual loss is sudden due to haemorrhage or fluid leakage from a subretinal neovascular membrane. The pathogenesis of AMD is not fully understood. Genetic studies have shown that the risk of AMD is related to polymorphisms of a number of immune related genes, including complement factor H (CFH)[7,8,9,10], complement component 2 and factor B (C2/CFB) [11], complement component 3 (C3)[12,13,14], Toll-like receptor (TLRs) [15], and fractalkine receptor (CX3CR1) genes[16,17,18,19], a recent study by Zerbib et al did not confirm the association between
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