MicroRNA‐155 negatively affects blood–brain barrier function during neuroinflammation
- 6 March 2014
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 28 (6), 2551-2565
- https://doi.org/10.1096/fj.13-248880
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. © FASEBKeywords
Funding Information
- Multiple Sclerosis Society of Canada
This publication has 45 references indexed in Scilit:
- Claudin-1 induced sealing of blood–brain barrier tight junctions ameliorates chronic experimental autoimmune encephalomyelitisActa Neuropathologica, 2011
- Interendothelial Claudin-5 Expression Depends on Cerebral Endothelial Cell–Matrix Adhesion by β1-IntegrinsJournal of Cerebral Blood Flow & Metabolism, 2011
- Comparison Evans Blue injection routes: Intravenous versus intraperitoneal, for measurement of blood–brain barrier in a mice hemorrhage modelJournal of Neuroscience Methods, 2011
- High and Low Molecular Weight Fluorescein Isothiocyanate (FITC)–Dextrans to Assess Blood-Brain Barrier Disruption: Technical ConsiderationsTranslational Stroke Research, 2010
- MicroRNA-155 Promotes Autoimmune Inflammation by Enhancing Inflammatory T Cell DevelopmentImmunity, 2010
- Mammalian microRNAs predominantly act to decrease target mRNA levelsNature, 2010
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Integrin connections to the cytoskeleton through talin and vinculinBiochemical Society Transactions, 2008
- Functional atlas of the integrin adhesomeNature, 2007
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001