Pleiotropic Roles of Scavenger Receptors in Circadian Retinal Phagocytosis: A New Function for Lysosomal SR-B2/LIMP-2 at the RPE Cell Surface

Abstract

The retinal phagocytic machinery resembles the one used by macrophages to clear apoptotic cells. However, in the retina, the permanent contact between photoreceptor outer segments (POS) and retinal pigment epithelial (RPE) cells requires a tight control of this circadian machinery. In addition to the known receptors synchronizing POS internalization, several others are expressed by RPE cells. Notably, scavenger receptor CD36 has been shown to intervene in the internalization speed. We thus investigated members of the scavenger receptor family class A SR-AI and MARCO and class B CD36, SR-BI and SR-B2/LIMP-2 using immunoblotting, immunohisto- and immunocytochemistry, lipid raft flotation gradients, phagocytosis assays after siRNA/antibody inhibition, RT-qPCR and western blot analysis along the light:dark cycle. All receptors were expressed by RPE cell lines and tissues and colocalized with POS, except SR-BI. All receptors were associated with lipid rafts, and even more upon POS challenge. SR-B2/LIMP-2 inhibition suggested a role in the control of the internalization speed similar to CD36. In vivo, MARCO and CD36 displayed rhythmic gene and protein expression patterns concomitant with the phagocytic peak. Taken together, our results indicate that CD36 and SR-B2/LIMP-2 play a direct regulatory role in POS phagocytosis dynamics, while the others such as MARCO might participate in POS clearance by RPE cells either as co-receptors or via an indirect process.

Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue

“…Using Sashimi plots (Fig. 10d ), we confirmed splicing defects for ITGα6 (skipped exon) and BEST1 (alternative 5′ splice sites), important genes associated with RPE homeostasis 43 , and for SCARB1 (skipped exon), recently described as involved in internalization of OS for RPE-mediated phagocytosis 44 .

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Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms

“…Smoothelin-like 2 has been shown to regulate efferocytosis and lactate metabolism in Sertoli cells of mice to achieve a homeostatic state ( 71 ). In the visual system, some scavenger receptors have a direct role in the tight regulation of the circadian rhythm by participating in the clearance of the outer segments of photoreceptors by retinal-pigment epithelial cells ( 72 ). Although this process is not strictly efferocytosis, it does involve scavenger receptors.…”

Efferocytosis in dendritic cells: an overlooked immunoregulatory process

“…The term “efferocytosis” was coined in 2006 by Peter Henson and his team, described the specialized phagocytosis of apoptotic cells ( 8 ). The cells responsible for efferocytosis encompass not only the professional phagocytes like macrophages and DCs but also include ‘non-professional’ phagocytes such as retinal pigment epithelial cells ( 9 ).…”