Abstract
At the earliest stage of activation, human polymorphonuclear neutrophils release vesicles derived directly from the cell surface. These vesicles, called ectosomes (PMN-Ect), expose phosphatidylserine in the outer membrane leaflet. They inhibit the inflammatory response of human monocyte-derived macrophages and dendritic cells to zymosan A (ZymA) and LPS and induce TGF-β1 release, suggesting a reprogramming toward a tolerogenic phenotype. The receptors and signaling pathways involved have not yet been defined. Here, we demonstrate that PMN-Ect interfered with ZymA activation of macrophages via inhibition of NFκB p65 phosphorylation and NFκB translocation. The MerTK (Mer receptor tyrosine kinase) and PI3K/Akt pathways played a key role in this immunomodulatory effect as shown using specific MerTK-blocking antibodies and PI3K inhibitors LY294002 and wortmannin. As a result, PMN-Ect reduced the transcription of many proinflammatory genes in ZymA-activated macrophages. In sum, PMN-Ect interacted with the macrophages by activation of the MerTK pathway responsible for down-modulation of the proinflammatory signals generated by ZymA.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Cell-Derived Microparticles / metabolism*
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Chromones / pharmacology
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Humans
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Inflammation / metabolism
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Lipopolysaccharides / pharmacology
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Macrophage Activation / drug effects
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Macrophage Activation / physiology*
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Macrophages / metabolism*
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Morpholines / pharmacology
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Neutrophils / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transcription Factor RelA / metabolism
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Transforming Growth Factor beta1 / metabolism
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Wortmannin
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Zymosan / pharmacology
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c-Mer Tyrosine Kinase
Substances
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Androstadienes
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Chromones
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Lipopolysaccharides
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Morpholines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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RELA protein, human
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Transcription Factor RelA
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Transforming Growth Factor beta1
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Zymosan
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Phosphatidylinositol 3-Kinases
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MERTK protein, human
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Receptor Protein-Tyrosine Kinases
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c-Mer Tyrosine Kinase
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Proto-Oncogene Proteins c-akt
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Wortmannin