Abstract
ABSTRACTDefects in phagocytosis and degradation of photoreceptor outer segments (POS) by the retinal pigment epithelium (RPE) are associated with aging and retinal disease. The daily burst of rod outer segment (ROS) phagocytosis by the RPE provides a unique opportunity to analyse phagosome processing in vivo. In mouse retinae, phagosomes containing stacked rhodopsin-rich discs were identified by immuno-electron microscopy. Early apical phagosomes stained with antibodies against both cytoplasmic and intradiscal domains of rhodopsin. During phagosome maturation, a remarkably synchronised loss of the cytoplasmic epitope coincided with movement to the cell body and preceded phagosome–lysosome fusion and disc degradation. Loss of the intradiscal rhodopsin epitope and disc digestion occurred upon fusion with cathepsin-D-positive lysosomes. The same sequential stages of phagosome maturation were identified in cultured RPE and macrophages challenged with isolated POS. Loss of the cytoplasmic rhodopsin epitope was insensitive to pH but sensitive to protease inhibition and coincided with the interaction of phagosomes with endosomes. Thus, during pre-lysosomal maturation of ROS-containing phagosomes, limited rhodopsin processing occurs upon interaction with endosomes. This potentially provides a sensitive readout of phagosome–endosome interactions that is applicable to multiple phagocytes.
Highlights
The retinal pigment epithelium (RPE) is a monolayer of highly polarised cells located between the photoreceptors and the fenestrated endothelium of the choriocapillaris, which forms part of the blood–retina barrier (Burke and Hjelmeland, 2005; Strauss, 2005)
EEA1 and Vps34) (Desjardins et al, 1994; Fratti et al, 2001; Gutierrez, 2013; Vieira et al, 2003). This ordered series of events can be circumvented by certain microorganisms and parasites to allow escape from degradation, and the speed and regulation of phagosome maturation varies amongst different phagocytes and different phagocytic cargoes
Little is known about the sequence of events leading to phagosome maturation in the RPE, despite the enormous phagocytic burden of these cells and the accumulation of the products of incomplete phagosome degradation that occurs with age and in some retinal degenerative diseases
Summary
The retinal pigment epithelium (RPE) is a monolayer of highly polarised cells located between the photoreceptors and the fenestrated endothelium of the choriocapillaris, which forms part of the blood–retina barrier (Burke and Hjelmeland, 2005; Strauss, 2005). The RPE performs essential roles for photoreceptor survival, which include absorption of light, protection against. RPE cells are largely postmitotic and so the daily ingestion of POS makes them the most phagocytic cells in the body, each cell digesting in excess of a billion photoreceptor discs in a 70-year human lifespan. This huge phagocytic load eventually takes its toll, and lipofuscin-containing deposits accumulate in all aging RPE and are marked in age-related macular disease (Kennedy et al, 1995). Defects in the engulfment of POS or their subsequent degradation are associated with inherited retinal degenerative diseases (Gibbs et al, 2003; Gordiyenko et al, 2010; Wavre-Shapton et al, 2013)
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