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Laboratory of Biochemistry, Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
Prompt phagocytosis of apoptotic cells prevents inflammatory and autoimmune responses to dying cells. We have previously shown that the blood anticoagulant factor protein S stimulates phagocytosis of apoptotic human B lymphoma cells by human monocyte-derived macrophages. In this study, we show that protein S must first undergo oxidative activation to stimulate phagocytosis. Binding of human protein S to apoptotic cells or to phosphatidylserine multilamellar vesicles promotes auto-oxidation of Cys residues in protein S, resulting in covalent, disulfide-linked dimers and oligomers that preferentially bind to and activate the human Mer tyrosine kinase (MerTK) receptor on the macrophages. The prophagocytic activity of protein S is eliminated when disulfide-mediated oligomerization is prevented, or when MerTK is blocked with neutralizing Abs. Protein S oligomerization is independent of phospholipid oxidation. The data suggest that membranes containing phosphatidylserine serve as a scaffold for protein S-protein S interactions and that the resulting auto-oxidation and oligomerization is required for the prophagocytic activity of protein S. In this way, apoptotic cells facilitate their own uptake by macrophages. The requirement for oxidative modification of protein S can explain why this abundant blood protein does not constitutively activate MerTK in circulating monocytes and tissue macrophages.
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1 Address correspondence and reprint requests to Dr. Emily Shacter, Center for Drug Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Building 29A, Room 2A-11, HFD-121, Bethesda, MD 20892-4555. E-mail address: emily.shacter{at}fda.hhs.gov
2 Abbreviations used in this paper: PS, phosphatidylserine; MerTK, Mer tyrosine kinase; CFDA, carboxyfluorescein diacetate, succinimidyl ester mixed isomer; PI, propidium iodide; PC, phosphatidylcholine; DOPS, dioleoyl PS; DOPC, dioleoyl PC; PLPS, 1-palmitoyl-2-linoleoyl-sn-glycero-3-[phospho-L-serine]; AAPH, 2.2'-azobis-2-methyl-propaimidaamide; (±)9-HODE, (±)-9-hydroxy-10E,12Z-octadecadienoic acid; IAA, iodoacetamide; NEM, N-ethylmaleimide; TnCl, taurine chloramine; sMer, soluble Mer; LMV, large multilamellar vesicle; oxPLPS, oxidized PLPS; LDS, lithium dodecyl sulfate.
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