title: MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.
abstract: Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders.
authors.affiliation: Department of Life, Health, and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK;
authors.forename: Miguel Alejandro
authors.initials: MA
authors.lastname: Lopez-Ramirez
authors.affiliation: Department of Life, Health, and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK;
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wu
authors.affiliation: Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK;
authors.forename: Gareth
authors.initials: G
authors.lastname: Pryce
authors.affiliation: Sheffield Institute for Translational Neuroscience and.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Simpson
authors.affiliation: Blood-Brain Barrier Research Group, Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
authors.affiliation: Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK;
authors.forename: Josh
authors.initials: J
authors.lastname: King-Robson
authors.affiliation: Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK;
authors.forename: Oliver
authors.initials: O
authors.lastname: Kay
authors.affiliation: Blood-Brain Barrier Research Group, Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: Department of Life, Health, and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK;
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hirst
authors.affiliation: Department of Neurology, Sheffield Teaching Hospitals National Health Service (NHS) Trust, University of Sheffield, Sheffield, UK; and.
authors.forename: Basil
authors.initials: B
authors.lastname: Sharrack
authors.affiliation: Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK;
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.affiliation: Department of Life, Health, and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK;
authors.forename: David Kingsley
authors.initials: DK
authors.lastname: Male
authors.affiliation: Center for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK;
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Michael
authors.affiliation: Department of Life, Health, and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK; nacho.romero@open.ac.uk.
authors.forename: Ignacio Andres
authors.initials: IA
authors.lastname: Romero
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009103:Multiple Sclerosis; D016608:Talin / Q000096:biosynthesis; D059467:Transcriptome; D015854:Up-Regulation; D016596:Vinculin / Q000096:biosynthesis
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016608:Talin; D016596:Vinculin
keywords: focal adhesion; junctional complex molecules; multiple sclerosis; neurovascular dysfunction