title: Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs.
abstract: The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC-EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-κB pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada;
authors.forename: Makon-Sébastien
authors.initials: MS
authors.lastname: Njock
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada;
authors.forename: Henry S
authors.initials: HS
authors.lastname: Cheng
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada;
authors.forename: Lan T
authors.initials: LT
authors.lastname: Dang
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany; and.
authors.forename: Maliheh
authors.initials: M
authors.lastname: Nazari-Jahantigh
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada;
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lau
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada;
authors.forename: Emilie
authors.initials: E
authors.lastname: Boudreau
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada;
authors.forename: Mark
authors.initials: M
authors.lastname: Roufaiel
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada;
authors.forename: Myron I
authors.initials: MI
authors.lastname: Cybulsky
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany; and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, Toronto, ON, Canada;
authors.forename: Jason E
authors.initials: JE
authors.lastname: Fish
mesh_terms: D002450:Cell Communication; D002460:Cell Line; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism*; D005110:Extracellular Space; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D035683:MicroRNAs; D016328:NF-kappa B
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