Abstract
Removal of apoptotic cells is an essential process for normal development and tissue maintenance. Importantly, apoptotic cells stimulate their phagocytosis by macrophages while actively suppressing inflammatory responses. Growth arrest specific gene 6 (Gas6) is involved in this process, bridging phosphatidylserine residues on the surface of apoptotic cells to the Axl/Mer family of tyrosine kinases which stimulate phagocytosis. Animals with mutations or loss of these receptors exhibit phenotypes reflective of impaired phagocytosis and a hyperactive immune response. We report that Gas6 induces phagocytosis in microglia through a novel non-classical phagocytic mechanism. Gas6 stimulates a type-II-related phagocytic response, but requires Vav phosphorylation and Rac activation, distinguishing it from the classical type II mechanism. Importantly, Gas6 suppressed lipopolysaccharide-induced expression of the inflammatory molecules IL-1beta and iNOS. Gas6 inhibited iNOS expression through suppression of promoter activity. The present data provide direct evidence for the role of Gas6 receptors in mediating an anti-inflammatory response to ligands found on apoptotic cells with the simultaneous stimulation of phagocytosis. These data provide a mechanistic explanation for the phenotype observed in animals lacking Axl/Mer receptors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Axl Receptor Tyrosine Kinase
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Brain / metabolism
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Cell Line / drug effects
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Cell Line / enzymology
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Cell Line / physiology
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Cytoskeleton / physiology
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Cytoskeleton / ultrastructure
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Gene Expression Regulation / drug effects
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Inflammation / genetics*
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Intercellular Signaling Peptides and Proteins / pharmacology*
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / genetics
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Lipopolysaccharides / toxicity
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Mice
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Microglia / drug effects*
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Microglia / enzymology
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Microglia / physiology
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / biosynthesis
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Nitric Oxide Synthase Type II / genetics
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Oncogene Proteins / physiology*
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Phagocytosis / drug effects*
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Phagocytosis / physiology
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Phosphorylation
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Protein Processing, Post-Translational
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-vav / metabolism
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Receptor Protein-Tyrosine Kinases / physiology*
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Recombinant Fusion Proteins / biosynthesis
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Transcription, Genetic / drug effects
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c-Mer Tyrosine Kinase
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rac GTP-Binding Proteins / metabolism
Substances
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Intercellular Signaling Peptides and Proteins
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Interleukin-1beta
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Lipopolysaccharides
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Oncogene Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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Recombinant Fusion Proteins
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Vav1 protein, mouse
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Mertk protein, mouse
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Receptor Protein-Tyrosine Kinases
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c-Mer Tyrosine Kinase
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rac GTP-Binding Proteins
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Axl Receptor Tyrosine Kinase
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AXL receptor tyrosine kinase, mouse