The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published online 13 November 2006 doi:10.1084/jem.20060370
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 12, 2613-2625
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ARTICLE

 Oxidized phosphatidylserine–CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells

Michael E. Greenberg1,3, Mingjiang Sun1, Renliang Zhang1,3, Maria Febbraio1, Roy Silverstein1, and Stanley L. Hazen1,2,3

1 Department of Cell Biology, 2 Department of Cardiovascular Medicine, and 3 Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, OH 44195

CORRESPONDENCE Stanley L. Hazen: hazens{at}ccf.org

The phagocytosis of apoptotic cells within an organism is a critical terminal physiological process in programmed cell death. Evidence suggests that apoptotic cell engulfment and removal by macrophages is facilitated by phosphatidylserine (PS) displayed at the exofacial surface of the plasma membrane; however, neither the macrophage receptors responsible for PS recognition, nor characterization of the PS molecular species potentially involved, have been clearly defined. We show that the class B scavenger receptor CD36 plays an essential role in macrophage clearance of apoptotic cells in vivo. Further, macrophage recognition of apoptotic cells via CD36 is shown to occur via interactions with membrane-associated oxidized PS (oxPS) and, to a lesser extent, oxidized phosphatidylcholine, but not nonoxidized PS molecular species. Mass spectrometry analyses of oxPS species identify structures of candidate ligands for CD36 in apoptotic membranes that may facilitate macrophage recognition. Collectively, these results identify oxPS–CD36 interactions on macrophages as potential participants in a broad range of physiologic processes where macrophage-mediated engulfment of apoptotic cells is involved.

Abbreviations used: CMFDA, 5-chloromethylfluorescein diacetate; Di-I, 1,1'- dioctadecyl-3,3,3',3'-tetramethlyindocarbocyanine perchlorate; IRES, internal ribosome entry signal; MPM, mouse peritoneal macrophage; MPO, myeloperoxidase; m/z, mass-to-charge ratio; oxLDL, oxidized low density lipoprotein; oxPC, oxidized PC; oxPCCD36, oxidized PC species possessing an sn-2 acyl group that incorporates a terminal {gamma}-hydroxy(or oxo)-{alpha},ß-unsaturated carbonyl; oxPS, oxidized PS; oxPSCD36, oxidized PS species possessing an sn-2 acyl group that incorporates a terminal {gamma}-hydroxy(or oxo)-{alpha},ß-unsaturated carbonyl; PAPS, 1-palmitoyl-2- arachidenoyl-sn-glycero-3-phosphoserine; PC, phosphatidylcholine; PLPS, 1-palmitoyl-2-lineoyl-sn-glycero-3-phosphoserine; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; POPS, 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphoserine; PS, phosphatidylserine; PSR, PS receptor; SUV, small unilamellar vesicle.


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