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T. Hisatomi, T. Sakamoto, K. Sonoda, C. Tsutsumi, H. Qiao, I. Yamanaka, T. Ishibashi; Clearance of Apoptotic Photoreceptors: Elimination of Apoptotic Debris into the Subretinal Space and Macrophage-mediated Phagocytosis after Retinal Detachment . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2944.
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Purpose: Effective phagocytotic clearance of apoptotic debris is fundamental to the maintenance of neural tissues during apoptosis. Retinal photoreceptors undergo apoptosis after retinal detachment (RD). While their induction phase of apoptosis has been well discussed, their phagocytotic process remains quite unclear. We examined the phagocytotic process of the apoptotic photoreceptors after RD. Methods: RD was produced by subretinal injection of sodium hyaluronate in Brown Norway rats. The eyes were enucleated on days 1, 3, 5, 7, 14, 28 after operation, and the sections were analysed by immunohistochemistry, transmission electron microscopy, immuno-electron microscopy and scanning electron microscopy. To examine the origin of phagocytes for apoptotic photoreceptors, we produced GFP chimera mice, which is C57/B6 mice transplanted with bone marrow cells of GFP-transgenic mouse. To elucidate the mechanism dependent for phagocyte-apoptotic debris recognition, blocking peptides or antibodies were administered in subretinal space. Results: The ultrastructural and immuno-phenotypic analysis demonstrated that apoptotic photoreceptors are selectively eliminated from their physiological localization, the outer nuclear layer, to the subretinal space, and then phagocytosed by monocyte-derived macrophages. Moreover, in chimeric mice expressing transgenic green fluorescent protein (GFP) in bone marrow derived cells, the local infiltration of macrophages could be detected after RD-induced photoreceptor apoptosis. A local injection of an antibody blocking the phosphatidylserine receptor (PSR) or a peptide (GRGDSP) blocking integrin avb3 revealed that phagocytotic clearance involves the PSR as well as integrin avb3 in vivo. While anti-PSR increased the frequency of apoptotic cells that fail to bind to macrophages, GRGDSP prevented the engulfment (but not the recognition) of apoptotic photoreceptor cells by macrophages. Conclusions: To our knowledge, this is the first report describing the mechanisms through which apoptotic photoreceptors are selectively eliminated from retina via a directional process in the subretinal space and phagocytosed by monocyte-derived macrophages.
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