title: Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation.
abstract: Pro-inflammatory cytokine-induced activation of nuclear factor, NF-κB has an important role in leukocyte adhesion to, and subsequent migration across, brain endothelial cells (BECs), which is crucial for the development of neuroinflammatory disorders such as multiple sclerosis (MS). In contrast, microRNA-146a (miR-146a) has emerged as an anti-inflammatory molecule by inhibiting NF-κB activity in various cell types, but its effect in BECs during neuroinflammation remains to be evaluated. Here, we show that miR-146a was upregulated in microvessels of MS-active lesions and the spinal cord of mice with experimental autoimmune encephalomyelitis. In vitro, TNFα and IFNγ treatment of human cerebral microvascular endothelial cells (hCMEC/D3) led to upregulation of miR-146a. Brain endothelial overexpression of miR-146a diminished, whereas knockdown of miR-146a augmented cytokine-stimulated adhesion of T cells to hCMEC/D3 cells, nuclear translocation of NF-κB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-κB activity upon cytokine activation through targeting two novel signaling transducers, RhoA and nuclear factor of activated T cells 5, as well as molecules previously identified, IL-1 receptor-associated kinase 1, and TNF receptor-associated factor 6. We propose brain endothelial miR-146a as an endogenous NF-κB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation.
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: Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK.
authors.forename: Camilla
authors.initials: C
authors.lastname: Cerutti
authors.affiliation: 1] Department of Life, Health and Chemical Sciences, Biomedical Research Network, The Open University, Milton Keynes, UK [2] Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lopez-Ramirez
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: 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: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
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: Susanne Ma
authors.initials: SM
authors.lastname: van der Pol
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: 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 Neurology, Sheffield Teaching Hospitals NHS Trust, University of Sheffield, Sheffield, UK.
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 K
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.
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation; D061346:Laser Capture Microdissection; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D014162:Transfection
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B