title: Exosome-delivered microRNAs modulate the inflammatory response to endotoxin.
abstract: MicroRNAs regulate gene expression posttranscriptionally and function within the cells in which they are transcribed. However, recent evidence suggests that microRNAs can be transferred between cells and mediate target gene repression. We find that endogenous miR-155 and miR-146a, two critical microRNAs that regulate inflammation, are released from dendritic cells within exosomes and are subsequently taken up by recipient dendritic cells. Following uptake, exogenous microRNAs mediate target gene repression and can reprogramme the cellular response to endotoxin, where exosome-delivered miR-155 enhances while miR-146a reduces inflammatory gene expression. We also find that miR-155 and miR-146a are present in exosomes and pass between immune cells in vivo, as well as demonstrate that exosomal miR-146a inhibits while miR-155 promotes endotoxin-induced inflammation in mice. Together, our findings provide strong evidence that endogenous microRNAs undergo a functional transfer between immune cells and constitute a mechanism of regulating the inflammatory response.
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, 4280 JMRB, 15 North Medical Drive East, Salt Lake City, Utah 84112, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Alexander
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, 4280 JMRB, 15 North Medical Drive East, Salt Lake City, Utah 84112, USA.
authors.forename: Ruozhen
authors.initials: R
authors.lastname: Hu
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, 4280 JMRB, 15 North Medical Drive East, Salt Lake City, Utah 84112, USA.
authors.forename: Marah C
authors.initials: MC
authors.lastname: Runtsch
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, 4280 JMRB, 15 North Medical Drive East, Salt Lake City, Utah 84112, USA.
authors.forename: Dominique A
authors.initials: DA
authors.lastname: Kagele
authors.affiliation: Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Mosbruger
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Tanya
authors.initials: T
authors.lastname: Tolmachova
authors.affiliation: Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
authors.forename: Miguel C
authors.initials: MC
authors.lastname: Seabra
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, 4280 JMRB, 15 North Medical Drive East, Salt Lake City, Utah 84112, USA.
authors.forename: June L
authors.initials: JL
authors.lastname: Round
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, 4280 JMRB, 15 North Medical Drive East, Salt Lake City, Utah 84112, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ward
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, 4280 JMRB, 15 North Medical Drive East, Salt Lake City, Utah 84112, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: O'Connell
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology*; D055354:Exosomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*
chemical_list: C526735:Ago2 protein, mouse; D060565:Argonaute Proteins; D008070:Lipopolysaccharides; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C532623:Mirn155 microRNA, mouse