MicroRNA‐155 negatively affects blood–brain barrier function during neuroinflammation. Issue 6 (6th March 2014)

• Record Type: Journal Article
• Authors: Lopez‐Ramirez, Miguel Alejandro; Wu, Dongsheng; Pryce, Gareth; Simpson, Julie E.; Reijerkerk, Arie; King‐Robson, Josh; Kay, Oliver; de Vries, Helga E.; Hirst, Mark C.; Sharrack, Basil; Baker, David; Male, David Kingsley; Michael, Gregory J.; Romero, Ignacio Andres
• Is Part Of: FASEB journal. Volume 28:Issue 6(2014)
• Page Start: 2551
• Page End: 2565
• Publication Date: 2014-03-06
• Subjects: multiple sclerosis -- neurovascular dysfunction -- junctional complex molecules -- focal adhesion; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.13-248880
• Languages: English
• ISSNs: 0892-6638

Abstract

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.—Lopez‐Ramirez, M. A., Wu, D., Pryce, G., Simpson, J. E., Reijerkerk, A., King‐Robson, J., Kay, O, de Vries, H. E., Hirst, M. C., Sharrack, B., Baker D., Male, D. K., Michael, G. J., Romero, I. A. MicroRNA‐155 negatively affects blood–brain barrier function during neuroinflammation. FASEB J . 28, 2551–2565 (2014). www.fasebj.org