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Sci Rep. 2017 Nov 7;7(1):14623. doi: 10.1038/s41598-017-15191-1.

Context-dependent compensation among phosphatidylserine-recognition receptors.

Author information

1
Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA.
2
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
3
Department of Urology, University of Virginia, Charlottesville, VA, USA.
4
Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
5
Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
6
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam, 52828, Korea.
7
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
8
Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA. ravi@virginia.edu.
9
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA. ravi@virginia.edu.
10
Inflammation Research Center, VIB, and the Department of Biomedical molecular Biology, Ghent University, Ghent, Belgium. ravi@virginia.edu.

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 -/- Bai1 Tg ) 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.

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