Murine Ccl2/Cx3cr1 Deficiency Results in Retinal Lesions Mimicking Human Age-Related Macular Degeneration

Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1857, USA.
Investigative Ophthalmology &amp Visual Science (Impact Factor: 3.66). 09/2007; 48(8):3827-36. DOI: 10.1167/iovs.07-0051
Source: PubMed

ABSTRACT Senescent Ccl2(-/-) mice are reported to develop cardinal features of human age-related macular degeneration (AMD). Loss-of-function single-nucleotide polymorphisms within CX3CR1 are also found to be associated with AMD. The authors generated Ccl2(-/-)/Cx3cr1(-/-) mice to establish a more characteristic and reproducible AMD model.
Single Ccl2- and Cx3cr1-deficient mice were crossbred to obtain Ccl2(-/-)/Cx3cr1(-/-) mice. Funduscopy, histopathology, retinal A2E quantification, proteomics, RT-PCR gene expression assay, immunochemistry, and Western blotting were used to examine the retina and to evaluate gene expression within the retinal tissue.
By 6 weeks of age, all Ccl2(-/-)/Cx3cr1(-/-) mice developed AMD-like retinal lesions, including drusen, retinal pigment epithelium alteration, and photoreceptor degeneration. Furthermore, choroidal neovascularization occurred in 15% of the mice. These degenerative lesions progressed with age. A2E, a major lipofuscin fluorophore that accumulated during AMD progression, was significantly higher in the Ccl2(-/-)/Cx3cr1(-/-) retina than in the wild-type retina. Complement cofactor was higher in the Ccl2(-/-)/Cx3cr1(-/-) RPE. Proteomics data indicated that four proteins were differentially expressed in Ccl2(-/-)/Cx3cr1(-/-) retina compared with control. One of these proteins, ERp29, an endoplasmic reticulum protein, functions as an escort chaperone and in protein folding.
The authors concluded that Ccl2(-/-)/Cx3cr1(-/-) mice develop a broad spectrum of AMD abnormalities with early onset and high penetrance. These observations implicate certain chemokines and endoplasmic reticulum proteins in AMD pathogenesis. Similar to the mechanism of neurodegeneration caused by dysfunction of endoplasmic reticulum proteins, decreased chaperoning may cause misfolded protein accumulation, leading to drusen formation and retinal degeneration.

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Available from: Jeffrey A Kowalak, Aug 24, 2015
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    • "Recent study conducted within the agerelated eye disease study 2 (AREDS2) project manifested a high macular pigment optical density (MPOD), indicator of macula health, in individuals supplemented with 10 mg of lutein and 2 mg of zeaxanthin per day, when compared with control group not receiving this supplementation (Bernstein et al. 2012). Concordant results were obtained from the mouse model, DKO mice, which develop focal retinal lesions that had clinical, biochemical, and pathological features of AMD, including the degeneration and atrophy of focal photoreceptors and RPE (lipofuscin accumulation, hypertrophy, and hypotrophy) as well as the presence of some drusenoid deposits (Ramkumar et al. 2010, 2013; Tuo et al. 2007; Zhang et al. 2013). Although this model lacks a macula (like all nonprimate models), it adopts the accumulation of A2E and the degeneration of focal photoreceptor and RPE, which are found in AMD. "
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    ABSTRACT: Cells in aerobic condition are constantly exposed to reactive oxygen species (ROS), which may induce damage to biomolecules, including proteins, nucleic acids and lipids. In normal circumstances, the amount of ROS is counterbalanced by cellular antioxidant defence, with its main components-antioxidant enzymes, DNA repair and small molecular weight antioxidants. An imbalance between the production and neutralization of ROS by antioxidant defence is associated with oxidative stress, which plays an important role in the pathogenesis of many age-related and degenerative diseases, including age-related macular degeneration (AMD), affecting the macula-the central part of the retina. The retina is especially prone to oxidative stress due to high oxygen pressure and exposure to UV and blue light promoting ROS generation. Because oxidative stress has an established role in AMD pathogenesis, proper functioning of antioxidant defence may be crucial for the occurrence and progression of this disease. Antioxidant enzymes play a major role in ROS scavenging and changes of their expression or/and activity are reported to be associated with AMD. Therefore, the enzymes in the retina along with their genes may constitute a perspective target in AMD prevention and therapy.
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    • ") and Dr . Philip Mur - phy of NIAID / NIH ( Combadiere et al . , 2003 ) , respectively . Generation of the Ccl2 À / À / Cx3cr1 À / À mice has been previ - ously described ( Tuo et al . , 2007 ) . Briefly , the Ccl2 À / À and Cx3cr1 À / À mice were used as the founder generation ( F 0 ) and were crossed to generate mice ( F 1 ) heterozygous for the Ccl2 and Cx3cr1 genes . The heterozygous mice were inter - crossed to obtain homozygous Ccl2 À / À Cx3cr1 À / À mice . Wild - type ( WT ) mice were C57BL / 6 background . Mice were"
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    • "Second, Fas/FasL mediated apoptosis is involved in photoreceptor degeneration (Dunaief et al., 2002; Zacks et al., 2007) and has been reported in DKO rd8 mice (Cao et al., 2010). A third factor might be related to the activation of microglia and M€ uller cells, which may cause adjacent photoreceptor death (Ross et al., 2007; Shen et al., 2011; Tuo et al., 2007; Zhou et al., 2009). In addition, light can also intensify the degenerative process of the photoreceptors (Ambati et al., 2003; Lai et al., 1978). "
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