title: Age- and light-dependent development of localised retinal atrophy in CCL2(-/-)CX3CR1(GFP/GFP) mice.
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(-/-)CX3CR1(GFP/GFP) mice on the C57BL/6J background. Retinal degeneration was not detected in CCL2(-/-)CX3CR1(GFP/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(-/-)CX3CR1(GFP/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(-/-)CX3CR1(GFP/GFP) mice respectively, but not in wild-type mice. All CCL2(-/-)CX3CR1(GFP/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(-/-)CX3CR1(GFP/GFP) mice. Markedly increased rhodopsin but reduced cone arrestin expression was observed in retinal outer layers in aged CCL2(-/-)CX3CR1(GFP/GFP) mice. GABA expression was reduced in the inner retina of aged CCL2(-/-)CX3CR1(GFP/GFP) mice. Significantly increased Müller glial and microglial activation was observed in CCL2(-/-)CX3CR1(GFP/GFP) mice compared to age-matched WT mice. Macrophages from CCL2(-/-)CX3CR1(GFP/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.
authors: Centre for Vision and Vascular Science, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors: Mei
authors: M
authors: Chen
authors: Jose R
authors: JR
authors: Hombrebueno
authors: Chang
authors: C
authors: Luo
authors: Rosana
authors: R
authors: Penalva
authors: Jiawu
authors: J
authors: Zhao
authors: Liza
authors: L
authors: Colhoun
authors: Sudha Pirya Soundara
authors: SP
authors: Pandi
authors: John V
authors: JV
authors: Forrester
authors: Heping
authors: H
authors: Xu
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2 / Q000172:deficiency* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008027:Light; D008264:Macrophages / Q000502:physiology; D008268:Macular Degeneration / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology; D018121:Receptors, Cytokine / Q000172:deficiency* / Q000235:genetics; D015728:Receptors, HIV / Q000172:deficiency* / Q000235:genetics; D012160:Retina / Q000473:pathology / Q000502:physiology*; D012162:Retinal Degeneration / Q000473:pathology*
chemical_list: D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D049452:Green Fluorescent Proteins
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