MicroRNA‐155 negatively affects blood–brain barrier function during neuroinflammation

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.

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

“…These data suggest that stabilization of ZO‐1 in the OGD/I group of cells was not mediated via miR‐155 direct targets Rheb and RhoA. Taken together, analyses of the cell junction proteins revealed that miR‐155 inhibition in the OGD‐subjected HBMECs led to ZO‐1 stabilization, which is in agreement with previous studies on neuroinflammation and experimental ischemia 18, 29…”

“…While CLDN5 is highly expressed in the brain endothelium, CLDN1 expression in cerebral capillaries is low and was only confirmed to be present in human, rat, and sheep BBB 3, 30, 31. Regardless of the low expression, CLDN1 function in human brain capillaries is critical for the maintenance of the BBB integrity during neuroinflammation and brain tumor 29, 44. In the experimental model of EAE, the induced expression of CLDN1 in only 30% to 50% of brain vasculature was sufficient for BBB strengthening and significant amelioration of the disease 45.…”

Les microARN

“…L'utilisation de ces biopuces appliquée à différents tissus provenant de patients atteints de SEP a ainsi mis en évidence une altération de l'expression de nombreux miARN au cours de la maladie. La détection des miARN a été réalisée à partir de tissus (sang total [13,14], tissu nerveux [15,16], hippocampe [17]), de cellules (cellules mononucléées du sang [18][19][20], lymphocytes B [21][22][23] et T [11,20,[23][24][25][26], monocytes [27], microglie [27], cellules endothéliales [28,29]) ou de fluides extracellulaires (sérum/plasma [12,18,[30][31][32][33], LCR [34]). Nous répertorions de manière systématique dans cette revue, l'ensemble des données issues de la littérature concernant les miARN SYNTHÈSE REVUES miR-155 -/- [37]) sont résistantes à l'induction d'une EAE.…”

“…Ce processus est également observé dans le dévelop-dans l'endothélium cérébral [29], dans le sérum [12] ainsi que dans les lésions cérébrales de patients SEP [15]. Or, son expression dans les cellules endothéliales module négativement les fonctions de la barrière hémato-encéphalique (avec une augmentation de sa perméabilité).…”

“…Or, son expression dans les cellules endothéliales module négativement les fonctions de la barrière hémato-encéphalique (avec une augmentation de sa perméabilité). Lopez-Ramirez et ses collègues ont en effet montré que la surexpression de miR-155 pouvait entraîner la dissociation de certains complexes de jonctions inter-endothéliales ou altérer les interactions cellule-matrice [29] (Figure 4). L'effet du transfert intercellulaire de miR-155 est l'une des hypothèses qui pourrait expliquer les méca-nismes à l'origine d'une perméabilité prolongée de la barrière hémato-encéphalique chez les patients atteints de SEP (Figure 4) -/-deviennent résistantes à l'EAE.…”