title: Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells.
abstract: Billions of inflammatory leukocytes die and are phagocytically cleared each day. This regular renewal facilitates the normal termination of inflammatory responses, suppressing pro-inflammatory mediators and inducing their anti-inflammatory counterparts. Here we investigate the role of the receptor tyrosine kinase (RTK) Mer and its ligands Protein S and Gas6 in the initial recognition and capture of apoptotic cells (ACs) by macrophages. We demonstrate extremely rapid binding kinetics of both ligands to phosphatidylserine (PtdSer)-displaying ACs, and show that ACs can be co-opsonized with multiple PtdSer opsonins. We further show that macrophage phagocytosis of ACs opsonized with Mer ligands can occur independently of a requirement for αV integrins. Finally, we demonstrate a novel role for Mer in the tethering of ACs to the macrophage surface, and show that Mer-mediated tethering and subsequent AC engulfment can be distinguished by their requirement for Mer kinase activity. Our results identify Mer as a receptor uniquely capable of both tethering ACs to the macrophage surface and driving their subsequent internalization.
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: I
authors.initials: I
authors.lastname: Dransfield
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zagórska
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Lew
authors.affiliation: MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors.forename: K
authors.initials: K
authors.lastname: Michail
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lemke
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000076202:c-Mer Tyrosine Kinase
chemical_list: D039564:Integrin alphaV; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase