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U. F. Luhmann, S. Robbie, P. M. G. Munro, V. Luong, T. Jingsheng, F. W. Fitzke, R. E. MacLaren, J. W. Bainbridge, C.-C. Chan, R. R. Ali; In vivo Phenotyping Reveals That the Age-Related Retinal Degeneration in Ccl2/Cx3cr1 Double Knockout Mice Is Focal and Closely Associated With Inner Retinal Autofluorescent Lesions. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6138.
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Microglia/macrophage activation and migration in the retina plays an important role in age-related macular degeneration (AMD) and are both controlled by cytokine signaling pathways. CX3CR1 receptor polymorphisms are associated with an increased risk to develop AMD and Cx3cr1 knockout mice show a late onset retinal degeneration, while senescent (>2 years) C-C cytokine 2 (Ccl2) knockout mice do not. Double knockout mice for both genes (CCDKO) develop an accelerated, early onset and more severe retinal phenotype compared to either of the single knockout mice. To understand the interaction of Ccl2 and Cx3cr1 signaling we assessed the progression of the age-related retinal phenotype in CCDKO mice in vivo.
CCDKO and aged-matched wildtype mice were kept under 12 h dark/light cycle and degenerative and vascular phenotypes were assessed at 1, 4 ,8 and 12 month of age using autofluorescent scanning laser ophthalmoscopy (AF-SLO), optical coherence tomography (OCT) and fundus fluorescein angiography (FFA).
By AF-SLO we identified two types of autofluorescent lesions in CCDKO mice from the age of 1 month onwards. Subretinal lesions were distributed evenly across the fundus whereas inner retinal lesions were mainly localized to the inferior retina and preceded an associated retinal degeneration and an increasing level of low grade vascular leakiness with tortuous vessels in the same area.
Our data suggest the described progressive retinal degeneration of CCDKO mice is more localized to the inferior retina and might be triggered by an external factor such as light. We propose that light-induced outer retinal damage may lead to inner retinal responses, possibly defective microglia leading to microglia-induced retinal degeneration, which may contribute to the pathogenesis of AMD.
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