Abstract
Phagocytes express multiple phosphatidylserine (PtdSer) receptors that recognize apoptotic cells. It is unknown whether these receptors are interchangeable or if they play unique roles during cell clearance. Loss of the PtdSer receptor Mertk is associated with apoptotic corpse accumulation in the testes and degeneration of photoreceptors in the eye. Both phenotypes are linked to impaired phagocytosis by specialized phagocytes: Sertoli cells and the retinal pigmented epithelium (RPE). Here, we overexpressed the PtdSer receptor BAI1 in mice lacking MerTK (Mertk−/−Bai1Tg) to evaluate PtdSer receptor compensation in vivo. While Bai1 overexpression rescues clearance of apoptotic germ cells in the testes of Mertk−/− mice it fails to enhance RPE phagocytosis or prevent photoreceptor degeneration. To determine why MerTK is critical to RPE function, we examined visual cycle intermediates and performed unbiased RNAseq analysis of RPE from Mertk+/+ and Mertk−/− mice. Prior to the onset of photoreceptor degeneration, Mertk−/− mice had less accumulation of retinyl esters and dysregulation of a striking array of genes, including genes related to phagocytosis, metabolism, and retinal disease in humans. Collectively, these experiments establish that not all phagocytic receptors are functionally equal, and that compensation among specific engulfment receptors is context and tissue dependent.
Highlights
Cell death is a crucial part of life
Sertoli cell phagocytosis is studied in the testes as apoptosis of developing germ cells occurs with sufficient regularity to quantify apoptotic corpse accumulation
In an attempt to determine if PtdSer receptors are functionally unique, we asked if PtdSer receptors are capable of compensating for one another in specialized phagocytes in vivo
Summary
BAI1-transgene reduces corpse accumulation in the testes of Mertk−/− mice. To determine whether distinct PtdSer receptors play unique roles in the process of engulfment, we designed a genetic approach to determine whether the overexpression of one receptor could rescue for the loss of another. BAI1 was unable to enhance phagocytosis in Mertk+/+ mice and importantly, the number of puncta in Mertk+/+ mice were equivalent to the number seen in Mertk+/− (Figure S3D) These data suggest that Bai1Tg expression is unable to rescue the RPE phagocytic defect observed in Mertk−/− mice. We validated the fatty acid elongase, Elovl[1] and the acetyl CoA synthetase, Acss[2], and found that the expression changes were reproducible, in both the original library and a fresh cohort of Mertk+/+ and Mertk−/− mice (Fig. 5E) Overall, these data suggest that MerTK might coordinate the phagocytic process at multiple levels from PtdSer binding, to cytoskeletal reorganization and phagosome maturation, as well as coordinating metabolic changes during phagocytosis (and potentially the visual cycle). Retinyl esters are notoriously difficult to extract and quantify, we developed a novel procedure
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