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vß3
From the Departments of Ophthalmology* and Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the Department of Ophthalmology, Kagoshima University School of Medicine, Kagoshima, Japan; Apoptosis and Immune System, Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France; and the Centre National de la Recherche Scientifique,¶ Institut Gustave Roussy, Villejuif, France
The effective phagocytotic clearance of apoptotic debris is fundamental to the maintenance of neural tissues during apoptosis. Retinal photoreceptors undergo apoptosis after retinal detachment. Although their induction phase of apoptosis has been well discussed, their phagocytotic process remains quite unclear. We herein demonstrate 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. This could be shown by an ultrastructural and immunophenotypic analysis. Moreover, in chimera mice expressing transgenic green fluorescent protein in bone marrow-derived cells, the local infiltration of macrophages could be detected after retinal detachment-induced photoreceptor apoptosis. The local injection of an antibody blocking the phosphatidylserine receptor (PSR) or a peptide (GRGDSP)-blocking integrin vß3 revealed that phagocytotic clearance involves the PSR as well as integrin vß3 in vivo. Importantly, the level of blockade obtained with these reagents was different. Although 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. To our knowledge, this is the first report describing the mechanisms through which apoptotic photoreceptors are selectively eliminated via a directional process in the subretinal space.
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