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S. Joly, M. Samardzija, M. Thiersch, C. Remé, A. Wenzel, C. Grimm; Roles of Beta3 and Beta5 Integrin Subunits in the Phagocytosis of Light-Damaged Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2503.
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Age-related Macular Degeneration (AMD) is a leading cause of blindness worldwide. Photoreceptor cell death in AMD is thought to result from a deficit in phagocytosis and/or digestion of photoreceptor outer segments by retinal pigment epithelium (RPE) cells, leading to accumulation of toxic products in the RPE. Alphav beta3 (b3) and alphav beta5 (b5) integrins were shown to be major regulators of retinal phagocytosis. The purpose of this study was to investigate the potential roles of b3 and b5 integrins in survival mechanisms of photoreceptors in the model of light-induced degeneration.
Adult pigmented wild type (WT) mice and b5 and b3 integrin knockout (KO) mice were exposed for 2 hours to 13,000 lux. Retinas and eyecups were collected for RNA isolation, followed by quantitative real-time RT-PCR, and for Western blotting analysis at different time points after light exposure (6 hrs, 24 hrs, 72 hrs, 5 days and 10 days) and compared with dark-maintained control animals. Endogenous expression changes of MCP1 (Monocyte Chemoattractant Protein 1), LIF (Leukemia Inhibitory Factor) and Caspase-1 mRNAs were followed in the different conditions. Whole eyes were sampled to follow retinal morphology change after light exposure.
Six hours after the offset of light, MCP1 gene expression was upregulated 20-fold in the neural retina of WT mice as compared to dark control animals not exposed to light. Lack of b3 integrin tremendously increased MCP1 levels 2000-fold above dark control b3 levels. This strong upregulation was maintained for 72 hrs after exposure in b3 KO mice. In contrast, b5 KO mice presented a transient 120 fold-increase in MCP1 gene expression that dropped to basal levels at 24 hrs after the end of light exposure. Interestingly, 6 hours after exposure, expression of LIF mRNA was more increased in b5 (1000-fold) than in b3 (75-fold) KO mice as compared to dark controls. At the same time point, expression of Caspase-1 was upregulated 16-fold in WT mice, 12-fold in b5 KO mice and 22-fold in b3 mutants relative to dark control mice. Caspase-1 mRNA displayed two phases of activation in WT mice, one peaking at 6 hrs (acute phase) and the other one, at 5 days (long-lasting phase) after light exposure.
Our data suggest that b3 integrin is involved in the regulation of MCP1 activation after photoreceptor degeneration. In addition, the upregulation of LIF transcription in b5 integrin KO and the relatively modest increase of Caspase-1 mRNA suggest that survival mechanisms may be affected by b5 integrin dysfunction.
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