Retinal atrophy, inflammation, phagocytic and metabolic disruptions develop in the MerTK-cleavage-resistant mouse model.

In the eye, cells from the retinal pigment epithelium (RPE) facing theneurosensory retina exert several functions that are all crucial for long-termsurvival of photoreceptors (PRs) and vision. Among those, RPE cells phagocytoseunder a circadian rhythm photoreceptor outer segment (POS) tips that areconstantly subjected to light rays and oxidative attacks. The MerTK tyrosinekinase receptor is a key element of this phagocytic machinery required for POSinternalization. Recently, we showed that MerTK is subjected to the cleavage ofits extracellular domain to finely control its function. In addition, monocytesin retinal blood vessels can migrate inside the inner retina and differentiateinto macrophages expressing MerTK, but their role in this context has not beenstudied yet. We thus investigated the ocular phenotype of MerTKcleavage-resistant (MerTK(CR)) mice to understand the relevance of thischaracteristic on retinal homeostasis at the RPE and macrophage levels. MerTK(CR)retinae appear to develop and function normally, as observed in retinal sections,by electroretinogram recordings and optokinetic behavioral tests. Monitoring ofMerTK(CR) and control mice between the ages of 3 and 18  months showed thedevelopment of large degenerative areas in the central retina as early as 4months when followed monthly by optical coherence tomography (OCT) plus fundusphotography (FP)/autofluorescence (AF) detection but not by OCT alone. Thedegenerative areas were associated with AF, which seems to be due to infiltratedmacrophages, as observed by OCT and histology. MerTK(CR) RPE primary culturesphagocytosed less POS in vitro, while in vivo, the circadian rhythm of POSphagocytosis was deregulated. Mitochondrial function and energy production werereduced in freshly dissected RPE/choroid tissues at all ages, thus showing ametabolic impairment not present in macrophages. RPE anomalies were detected byelectron microscopy, including phagosomes retained in the apical area andvacuoles. Altogether, this new mouse model displays a novel phenotype that couldprove useful to understanding the interplay between RPE and PRs in inflammatoryretinal degenerations and highlights new roles for MerTK in the regulation of theenergetic metabolism and the maintenance of the immune privilege in the retina.