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

• Published in: Acta neuropathologica 2015-05, Vol.129 (5), p.639
• Main Authors: Haarmann, Axel, Nowak, Eva, Deiß, Annika, van der Pol, Susanne, Monoranu, Camelia-Maria, Kooij, Gijs, Müller, Nora, van der Valk, Paul, Stoll, Guido, de Vries, Helga E, Berberich-Siebelt, Friederike, Buttmann, Mathias
• Format: Article
• Language: English
• Subjects: Antigens; Brain; Cell adhesion & migration; Dextrans; Endothelium; Integrins; Kinases; Multiple sclerosis; Permeability
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-015-1417-0

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 [alpha]-4/[beta]-1, the molecular binding partner of sVCAM-1, and that sVCAM-1 directly impairs BBB function by inducing intracellular signalling events through integrin [alpha]-4. Primary human brain microvascular endothelial cells showed low to moderate integrin [alpha]-4 and strong [beta]-1 but no definite [beta]-7 expression in vitro and in situ. Increased brain endothelial integrin [alpha]-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 [alpha]-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.