Epigentic modification of blood brain barrier function

Lopez-Ramirez MA, Wu D, Pryce G, Simpson JE, Reijerkerk A, King-Robson J, Kay O, de Vries HE, Hirst MC, Sharrack B, Baker D, Male DK, Michael GJ, Romero IA. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation. FASEB J. 2014 Mar. [Epub ahead of print]

Blood-brain barrier (BBB) dysfunction is a hallmark of neurologic 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.

Mir 155 is one of the microRNA that has epigenetic effects. In this study we demonstrate that mir155 is expressed within the blood vessels of the brain and blockade of its action could modulate the permeability of the blood vessels and could block the effects of a number of molecules that allow white blood cells to get into the brain. We also showed that loss of Mir 155 could influence susceptibility to EAE, however this has been shown before. But in that case it was believed that Mir155 was working on blood vessels this study shows that it can work in the blood vessels also. So now we have further insight into the processes by which blood cells get into the brain and offers therapeutic options. However Mir155 is not the only microRNA to do this.

CoI. Involved work of Team G  

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