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© Research
Publication : Acta neuropathologica

Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin α-4-transduced outside-in signalling

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Acta neuropathologica - 27 Mar 2015

Haarmann A, Nowak E, Deiß A, van der Pol S, Monoranu CM, Kooij G, Müller N, van der Valk P, Stoll G, de Vries HE, Berberich-Siebelt F, Buttmann M

Link to Pubmed [PMID] – 25814153

Acta Neuropathol. 2015 May;129(5):639-52

Human brain microvascular endothelial cells forming the blood-brain barrier (BBB) release soluble vascular cell adhesion molecule-1 (sVCAM-1) under inflammatory conditions. Furthermore, sVCAM-1 serum levels in untreated patients with multiple sclerosis (MS) correlate with a breakdown of the BBB as measured by gadolinium-enhanced MRI. To date, it is unknown whether sVCAM-1 itself modulates BBB permeability. Here, we provide evidence that human brain endothelium expresses integrin α-4/β-1, the molecular binding partner of sVCAM-1, and that sVCAM-1 directly impairs BBB function by inducing intracellular signalling events through integrin α-4. Primary human brain microvascular endothelial cells showed low to moderate integrin α-4 and strong β-1 but no definite β-7 expression in vitro and in situ. Increased brain endothelial integrin α-4 expression was observed in active MS lesions in situ and after angiogenic stimulation in vitro. Exposure of cultured primary brain endothelial cells to recombinant sVCAM-1 significantly increased their permeability to the soluble tracer dextran, which was paralleled by formation of actin stress fibres and reduced staining of tight junction-associated molecules. Soluble VCAM-1 was also found to activate Rho GTPase and p38 MAP kinase. Chemical inhibition of these signalling pathways partially prevented sVCAM-1-induced changes of tight junction arrangement. Importantly, natalizumab, a neutralising recombinant monoclonal antibody against integrin α-4 approved for the treatment of patients with relapsing-remitting MS, partially antagonised the barrier-disturbing effect of sVCAM-1. In summary, we newly characterised sVCAM-1 as a compromising factor of brain endothelial barrier function that may be partially blocked by the MS therapeutic natalizumab.

https://www.ncbi.nlm.nih.gov/pubmed/25814153