Regulation of the rhythmic diversity of daily photoreceptor outer segment phagocytosis in vivo

Outer segment phagocytosis (OSP) is a highly‐regulated, biological process wherein photoreceptor outer segment (OS) tips are cyclically phagocytosed by the adjacent retinal pigment epithelium (RPE) cells. Often an overlooked retinal process, rhythmic OSP ensures the maintenance of healthy photoreceptors and vision. Daily, the photoreceptors renew OS at their base and the most distal, and likely oldest, OS tips, are phagocytosed by the RPE, preventing the accumulation of photo‐oxidative compounds by breaking down phagocytosed OS tips and recycling useful components to the photoreceptors. Light changes often coincide with an escalation of OSP and within hours the phagosomes formed in each RPE cell are resolved. In the last two decades, individual molecular regulators were elucidated. Some of the molecular machinery used by RPE cells for OSP is highly similar to mechanisms used by other phagocytic cells for the clearance of apoptotic cells. Consequently, in the RPE, many molecular regulators of retinal phagocytosis have been elucidated. However, there is still a knowledge gap regarding the key regulators of physiological OSP in vivo between endogenous photoreceptors and the RPE. Understanding the regulation of OSP is of significant clinical interest as age‐related macular degeneration (AMD) and inherited retinal diseases (IRD) are linked with altered OSP. Here, we review the in vivo timing of OSP peaks in selected species and focus on the reported in vivo environmental and molecular regulators of OSP.