title: Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin α-4-transduced outside-in signalling.
abstract: 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.
authors: Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany, haarmann_a@ukw.de.
authors: Axel
authors: A
authors: Haarmann
authors: Eva
authors: E
authors: Nowak
authors: Annika
authors: A
authors: Deiß
authors: Susanne
authors: S
authors: van der Pol
authors: Camelia-Maria
authors: CM
authors: Monoranu
authors: Gijs
authors: G
authors: Kooij
authors: Nora
authors: N
authors: Müller
authors: Paul
authors: P
authors: van der Valk
authors: Guido
authors: G
authors: Stoll
authors: Helga E
authors: HE
authors: de Vries
authors: Friederike
authors: F
authors: Berberich-Siebelt
authors: Mathias
authors: M
authors: Buttmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology*; D018929:Cell Culture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D039441:Integrin alpha4 / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000069442:Natalizumab / Q000494:pharmacology; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D007155:Immunologic Factors; D019012:Integrin beta1; D000069442:Natalizumab; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4