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Jayeeta Roychoudhury, Teresa Doggett, Jingsheng Tuo, Defen Shen, Jun Zhang, Chi-Chao Chan, Grant Kolar, Thomas Ferguson; Age-related Macular Degeneration (AMD)-like Retinal Lesions and Vision Impairment in Ccl2/Cx3cr1 Double Deficient Mice are Mediated by Fas/FasL Interactions. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3010.
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Mice deficient in Ccl2 and Cx3cr1 (Ccl2-/-/Cx3cr1-/-) develop AMD-like features including abnormal retinal pigment epithelium, photoreceptor or outer retinal degeneration, A2E accumulation and vision impairment. These studies were undertaken to determine the mechanisms involved in the development of pathology in this mouse strain.
FasL-mediated apoptotic pathway was inactivated by crossing Ccl2-/-/Cx3cr1-/- mice to FasL-deficient (gld) mice to generate Ccl2-/-/Cx3cr1-/-/gld mice. FasL, Fas receptor and terminal deoxynucleotidyl transferase of dUTP nick end labeling (TUNEL) staining were performed on retinal sections.Fundoscopy, histopathology, immunohistochemistry and Western blotting were used to examine the eyes of these strains. A2E, a major lipofuscin component that accumulates in human AMD eyes was quantified in both mouse strains. The role of the accumulation A2E on FasL-mediated apoptosis and retinal pathology in Ccl2-/-/Cx3cr1-/- mice, was examined in mice fed with high w-3 polyunsaturated (n-3) fatty acids.
Examination of the retina in Ccl2-/-/Cx3cr1-/- mice revealed a significant number of apoptotic cells and increased expression of the proapoptotic protein FasL in the retinal lesions suggesting a role for Fas-FasL mediated apoptosis in this disease. FasL-deficient Ccl2-/-/Cx3cr1-/-/gld mice exhibited no retinal pathology and had normal visual function. Histological and ultra structural examination revealed normal retina/RPE architecture and other signs of disease noted in Ccl2-/-/Cx3cr1-/- mice such as deposition of complement C3d, depressed Erp29 expression, increased expression of the ER stress protein GrPBiP-78, and the production of anti-retinal antibodies were absent. Interestingly, both Ccl2-/-/Cx3cr1-/- and Ccl2-/-/Cx3cr1-/-/gld mice had elevated levels of A2E in the eye. Lowering A2E levels in Ccl2-/-/Cx3cr1-/- mice with a high n-3 fatty acid diet reduced FasL expression, apoptosis and retinal pathology.
Retinal pathology in the Ccl2-/-/Cx3cr1-/- miceis initiated by the accumulation of A2E leading Fas/FasL mediated apoptosis. All the major pathologic features of the model occur following apoptosis induced by FasL in this model. Thus, targeting the Fas/FasL pathway may be a viable approach to treating blinding eye disorders including AMD.
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