TY - JOUR
T1 - Context-dependent compensation among phosphatidylserine-recognition receptors
AU - Penberthy, Kristen K.
AU - Rival, Claudia
AU - Shankman, Laura S.
AU - Raymond, Michael H.
AU - Zhang, Jianye
AU - Perry, Justin S.A.
AU - Lee, Chang Sup
AU - Han, Claudia Z.
AU - Onengut-Gumuscu, Suna
AU - Palczewski, Krzysztof
AU - Lysiak, Jeffrey J.
AU - Ravichandran, Kodi S.
N1 - Funding Information:
We would like to thank all of the members of the Ravichandran Lab for their advice and support. We would also like to thank Tal Burstyn-Cohen for her assistance in developing dissection techniques. We would like to acknowledge the support of the University of Virginia Research Histology Core and Biological Tissue Repository Facility for preparing testicular sections and cleaved-caspase 3 staining, respectively. We would like to thank the University of Virginia Genomics Core Facility and AnhThu Nguyen for her preparation of the cDNA libraries for RNAseq. We would like to thank Emily Farber for running the Illumina NextSeq analysis. We would like to thank Alex Koeppel and the University of Virginia Bioinformatics Core for performing the DESeq. 2 analysis of the raw RNAseq data. The stereology data described in this manuscript was gathered on an “MBF Bioscience and Zeiss microscope system for stereology and tissue morphology” funded by National Institutes of Health grant 1S10RR026799-01. This work is supported by grants to KSR from NIGMS (GM064709), NHLBI (P01HL120840), and the Center for Cell Clearance/University of Virginia School of Medicine. KKP is supported by an NHLBI F30 award (F30 HL126385) and previously by the NIH T32 Immunology Training Grant (T32 AI007496).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85033406681&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-15191-1
DO - 10.1038/s41598-017-15191-1
M3 - Article
C2 - 29116131
AN - SCOPUS:85033406681
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 14623
ER -