αvβ5 Integrin Receptors at the Apical Surface of the RPE: One Receptor, Two Functions

Photoreceptors and retinal pigment epithelial (RPE) cells, two adjacent cells types of the outer retina, interact with each other functionally in numerous ways. Maintenance of permanent retinal adhesion and cyclic phagocytosis of shed photoreceptor outer segment fragments (POS) by RPE cells are two forms of these interactions that are crucial for vision. RPE cells form a polarized monolayer and extend apical microvilli that ensheath photoreceptor outer segments. Outer segments consist of stacked membranous disks containing the phototransduction machinery and are permanently renewed. To maintain constant outer segment length photoreceptors eliminate their most aged tips by daily shedding (Young, 1967), which precedes a burst of phagocytosis by the RPE that efficiently clears POS from the subretinal space and recycles many of their components (Young and Bok, 1969). POS shedding and subsequent phagocytosis by RPE cells are critical for photoreceptor cell function and long term survival. Indeed, complete failure to ingest POS by RPE cells from the Royal College of Surgeons (RCS) rat strain causes debris accumulation and rapid photoreceptor degeneration (Mullen and LaVail, 1976; Edwards and Szamier, 1977). Clearing their daily load of POS renders post-mitotic RPE cells the most active phagocytes in the body. Synchronized POS clearance is tightly regulated and any delay in completing the shedding or digestion process can cause accumulation of autofluorescent lipofuscin inclusion bodies containing a complex mix of proteins and lipids that likely result from incomplete turnover of POS material (Feeney, 1978). In vitro studies have recently shown that lipofuscin components may directly impair RPE function and viability (Finnemann et al., 2002; Schutt et al., 2006). These data suggest that defective digestion of POS by RPE cells may contribute to development or progression of age-related retinal diseases such as age-related macular degeneration. Outer segment renewal in higher vertebrates is synchronized by circadian rhythms influenced by the daily dark-light cycle (Goldman et al., 1980). Animal studies in rod- or cone-dominant species revealed that rods mainly shed their POS within 2 hours after onset of light and cones shed within 2 hours after dusk (LaVail, 1976; Young, 1977). The increase in the number of phagosomes present in RPE cells at these two time points suggests a peak in phagocytic activity every 12 or 24 hours for RPE cells depending on whether they serve rods, cones or both. No untimely phagocytosis has been observed so far, suggesting that RPE cells may downregulate their phagocytic activity if not “on duty”. Retinal adhesion is equally essential for vision as daily POS phagocytosis but must be maintained permanently. Different factors such as intraocular pressure and a net fluid transport from retina to RPE contribute to retinal adhesion. Additionally, receptors expressed at the RPE apical surface are thought to adhere to ligands in the interphotoreceptor matrix (IPM), a complex mix of proteins and proteoglycans filling the subretinal space and ensheathing cone and rod POS (Hageman et al., 1995; Hollyfield et al., 1989; Hollyfield et al., 1999). IPM proteoglycan rearrangement and RPE microvilli collapse are early responses to retinal detachment that, if persistent, result in RPE dedifferentiation and proliferation, POS degeneration and photoreceptor cell death by apoptosis (Cook et al., 1995). Despite their obvious importance for vision, we still know little about mechanisms that regulate the rhythm of RPE phagocytosis and RPE surface receptors or IPM ligands that mediate retinal adhesion.