title: MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium.
abstract: Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation.
authors.affiliation: Department of Life, Health and Chemical Sciences, Biomedical Research Network, Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.|Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Camilla
authors.initials: C
authors.lastname: Cerutti
authors.affiliation: Nottingham University Hospitals, QMC, Queen's Medical Centre, Nottingham, NG7 2UH, UK.|Division of Rehabilitation Medicine, Royal Derby Hospital, Uttoxeter Road, Derby DE22 3NE, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Edwards
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, 1007 MB Amsterdam, the Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: Department of Neuroscience, Sheffield University, 385a Glossop Road, Sheffield, S10 2HQ, UK.
authors.forename: Basil
authors.initials: B
authors.lastname: Sharrack
authors.affiliation: Department of Life, Health and Chemical Sciences, Biomedical Research Network, Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: David K
authors.initials: DK
authors.lastname: Male
authors.affiliation: Department of Life, Health and Chemical Sciences, Biomedical Research Network, Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
mesh_terms: D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002460:Cell Line; D019040:E-Selectin / Q000235:genetics; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D033081:Shear Strength; D000074084:THP-1 Cells; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; D019040:E-Selectin; C573415:IFNG protein, human; C527111:MIRN126 microRNA, human; D035683:MicroRNAs; C546936:SELE protein, human; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D007371:Interferon-gamma