Age-dependent induction of ER stress in retinal pigment epithelium impairs phagocytosis via ADAM17-dependent MERTK shedding.

Retinal pigment epithelium (RPE) plays a crucial role in maintaining visual function by phagocytosing photoreceptor outer segments (POS). Age-related decline in RPE phagocytic activity has been linked to the development of degenerative retinal diseases, including age-related macular degeneration (AMD). However, the underlying mechanisms of RPE phagocytic dysfunction remain poorly understood. In this study, we examined age-related induction of endoplasmic reticulum (ER) stress in RPE cells and its association with POS phagocytosis using tissues from middle-aged mice and cultured RPE cells. In the RPE-choroid complex of 12-month-old mice, ER stress marker proteins were significantly upregulated compared to younger mice. Notably, this increase was absent in the neural retina at the same age. In cultured RPE cells, pharmacological induction of ER stress by tunicamycin (Tm) significantly reduced both phagocytic activity and lysosomal function. Treatment with sodium 4-phenylbutyrate, a chemical chaperone, and transfection with chaperone protein-inducible plasmids alleviated the ER stress-induced phagocytic dysfunction in RPE cells. In the lysates of ER stress-induced RPE cells, the extracellular domain of Mer tyrosine kinase receptor (MERTK) and phosphorylation of focal adhesion kinase were significantly decreased. Mechanistically, ER stress promoted the maturation of a disintegrin and metalloprotease 17 (ADAM17) through Ca(2+)-dependent activation of the Furin protease, leading to MERTK shedding. Furthermore, ADAM17 knockdown attenuated the Tm-induced impairment of POS internalization. Collectively, our findings suggest that ER stress impairs RPE phagocytosis through an integrated mechanism and may contribute to the pathogenesis of AMD.