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P. G. McMenamin, T. G. Humphries, J. Kezic, S. Cherepanoff, S. H. Sarks; Accumulation of Macrophages in the Subretinal Space: Correlation With Age, Pigmentation and Cx3Cr1 Genotype in the Mouse Eye and With Age/AMD Pathology in Humans. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3868.
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Increasing evidence points to a possible role for the immune system in the pathogenesis of age-related macular degeneration (AMD). The accumulation of Cx3cr1+ macrophages in the subretinal space of Cx3cr1-deficient mice has previously been proposed to represent a ‘model’ of AMD. The purpose of this study was firstly to investigate the effects of three variables: age, pigmentation and Cx3r1-deficiency on the accumulation of macrophages/microglia in the subretinal space. Furthermore, preliminary correlation of numbers of subretinal macrophage (SrM) numbers with degenerative changes in aged human eyes and with various stages of AMD was performed.
Fifty four mice were grouped by age (young, 8-37 wks; middle aged, 46-60 wks; old, 70-85 wks), genotype, (Cx3cr1gfp/gfp or Cx3cr1gfp/+) and phenotype (pigmented, C57Bl/6 or albino, BALB/c) and examined using in vivo (Heidelberg Retinal angiography), resin sections, and immunophenotypical analysis for the presence of SrMs/microglia. Normal human eyes (n=12) were grouped by age and examined histologically for the presence of SrM. A further 2 eyes from each of the 5 stages of AMD pathogenesis were examined for the presence of SrM cells.
SrM numbers increased with age in both strains of mice but a more marked increase was noted in albino mice. Cx3cr1 deficiency resulted in a significant increase in SrMs only in the oldest age group of albino mice. CD45+, Cd11b+ and CD68+ dendriform microglia, not normally present in the photoreceptor layer, were noted in this zone in aged Cx3cr1gfp/+ and Cx3cr1gfp/gfp BALB/c mice as well as large, pleomorphic, lipofuscin-containing macrophages which tended to accumulate closer to the RPE interface. Age and albinism, but not Cx3cr1 deficiency, were associated with mild degenerative changes in the RPE, however none of these changes were conclusively similar to human AMD. No major degenerative changes in the outer retina of older mice was noted. In human eyes SrM numbers increased in normal human eyes with age but not in AMD affected eyes until severe pathology (atrophy or neovascularisation) had developed.
This study suggests that although deficiency in the Cx3cr1 gene may result in accelerated accumulation of SrMs in older albino mice, it does not resemble AMD-like pathology. Preliminary studies in human do not appear to implicate SrMs in the pathogenesis of AMD. Rather their increase in numbers in the end stages of AMD are more likely a secondary consequence of AMD pathology.
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