Autophagy Activation in the Injured Photoreceptor Inhibits Fas-Mediated Apoptosis

Separation of the retina from the retinal pigment epithelium (RPE) is a common form of injury that may occur alone (retinal detachment) or as a result of other blinding disease processes such as age-related macular degeneration or diabetic retinopathy. Despite significant advances in the medical and surgical management of retina–RPE separation, patients often lose vision, primarily due to the death of photoreceptors.1,2 We previously showed that the main event causing photoreceptor death is the activation of the Fas receptor and the downstream cascade of caspases 8, 3, 7, and 9.3–5 Preventing Fas pathway activity provides significant protection against separation-induced death of the photoreceptors. Although Fas-mediated apoptosis is activated rapidly after retina–RPE separation, a surprising number of photoreceptors survive for extended periods of time. This is best exemplified by the clinical observation that patients with retinal detachments affecting central vision generally recover near-normal vision if the detachment is repaired within 1 week.6,7 If repair is delayed beyond 1 week, visual outcomes become significantly poorer. This suggests that early in the course of the detachment, antiapoptotic pathways are activated within the retina to counteract the effect of proapoptotic signals and that they are responsible for the therapeutic window of opportunity for reattachment.8 Autophagy is a complex process that results in the autovacuolization of damaged or redundant cellular components. These vacuoles (i.e., autophagosomes) fuse with lysosomes and their contents are enzymatically degraded and released back into the cell.9 Autophagy activation typically occurs during periods of metabolic stress, usually serving as a cytoprotective process.10 Autophagy has been shown to occur in photoreceptors as part of basal processing of rod outer segments11 as well as in animal models of hereditary retinal degeneration and in models of oxidative stress.12–14 The role of autophagy in these settings is not well defined. We examined the role of autophagy and its control of photoreceptor apoptosis using a well-established rodent model of experimental retina–RPE separation. Our findings demonstrate that retinal detachment results in the activation of autophagy in photoreceptors. Similar to apoptosis, detachment-induced autophagy activity is Fas dependent. In detached retinas, autophagy acts as a prosurvival pathway through negative inhibition of apoptosis. Our data suggest a novel mechanism by which autophagy can be activated and regulate photoreceptor apoptosis.