Mertk Activation During RPE Phagocytosis in Vivo Requires αVβ5 Integrin

Abstract

Daily phagocytosis of shed photoreceptor outer segment fragments (POS) is a key task of the retinal pigment epithelium (RPE) in the retina. Lack or inefficiency of daily POS clearance causes early onset, rapid, and complete retinal degeneration in experimental animals and likely contributes to human blinding diseases such as retinitis pigmentosa and age-related macular degeneration (Dowling and Sidman, 1962, Gal et al., 2000). The phagocytic mechanism of the RPE belongs to a group of conserved non-inflammatory clearance pathways that mediate recognition and engulfment of apoptotic cells in both non-professional and professional phagocytic cells, such as fibroblasts and macrophages, respectively (Finnemann and Rodriguez-Boulan, 1999). These pathways share the use of phagocyte cell surface receptors such as the lipid scavenger receptor CD36 (Ryeom et al., 1996), the integrin adhesion receptor αv β5 (Finnemann et al., 1997; Miceli et al., 1997; Lin and Clegg, 1998) and the receptor tyrosine kinase Mer (MerTK) (D’Cruz et al., 2000; Nandrot et al., 2000). In vitro phagocytosis assays studying primary or permanent RPE in culture fed with isolated POS suggest that CD36 and MerTK participate in the engulfment step of the phagocytic process (Chaitin and Hall, 1983; Finnemann and Silverstein, 2001), while αv β5 integrin promotes POS recognition/binding and initiates a downstream cytoplasmic signaling cascade in the RPE (Finnemann et al., 1997). However, the precise function of these receptors and their roles in the intact retina are so far only poorly understood. Most recently, we have begun to study phagocytosis and receptor activity in animal models that lack αv β5 integrin or MerTK to determine how these different plasma membrane receptors of the RPE functionally interact to coordinate particle uptake.