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H. Chen, N. Du, G. Suyeoka, A. H. Neufeld; Iron Overload Decreases Phagocytosis Function of RPE Cells by Inhibiting Integrin vβ5. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4178.
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Iron is an essential element for many metabolic processes, but excess iron generates highly reactive hydroxyl radicals which damage lipid membranes, proteins and nucleic acids. Recent studies have suggested that iron may contribute to the pathogenesis of age-related macular degeneration (AMD). In prior studies, we demonstrated significantly increased iron levels and changes in iron homeostasis proteins in aged rodent retinal pigment epithelium (RPE)/choroid. To characterize how age-related increases in iron may affect the functions of the RPE, we studied the effects of iron overload on the phagocytosis of photoreceptor outer segments (POS).
ARPE-19 cells were cultured in the presence of increasing concentrations of iron-NTA and assayed for phagocytosis, binding and internalization of labeled POS. The amount of integrin vβ5 complex on the ARPE-19 cell surface was detected by flow cytometry. The binding of integrin vβ5 to POS and activation of downstream signal focal adhesion kinase (FAK) were detected by immunofluorescence and immunoprecipitation.
Exposure of ARPE-19 cells to increased iron markedly decreased phagocytosis activity of POS. In addition, iron overload decreased both the binding and the internalization of POS by RPE cells. On the RPE cell surface, integrin vβ5 is responsible for the binding of POS. Using flow cytometry, we found that iron overload decreased the amount of integrin vβ5 complex on the RPE cell surface. Consequently, iron overload also decreased the binding of POS to integrin vβ5. Activation of FAK is essential for the internalization of POS by RPE cells. Iron overload decreased the binding of FAK to integrin vβ5 and subsequently decreased the activation of FAK.
Iron overload, which occurs in the aged RPE/choroid, decreases the phagocytic function of RPE cells by down-regulating integrin vβ5, thus reducing the activation of its downstream signal FAK. Increased oxidative stress and decreased phagocytosis caused by elevated iron levels may lead to decreased function in the RPE of old eyes and contribute to the pathogenesis of AMD.
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