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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-30108

Huppert, J; Closhen, D; Croxford, A; White, R; Kulig, P; Pietrowski, E; Bechmann, I; Becher, B; Luhmann, H J; Waisman, A; Kuhlmann, C R W (2010). Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB Journal, 24(4):1023-1034.

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Abstract

Recently T-helper 17 (Th17) cells were demonstrated to disrupt the blood-brain barrier (BBB) by the action of IL-17A. The aim of the present study was to examine the mechanisms that underlie IL-17A-induced BBB breakdown. Barrier integrity was analyzed in the murine brain endothelial cell line bEnd.3 by measuring the electrical resistance values using electrical call impedance sensing technology. Furthermore, in-cell Western blots, fluorescence imaging, and monocyte adhesion and transendothelial migration assays were performed. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. IL-17A induced NADPH oxidase- or xanthine oxidase-dependent reactive oxygen species (ROS) production. The resulting oxidative stress activated the endothelial contractile machinery, which was accompanied by a down-regulation of the tight junction molecule occludin. Blocking either ROS formation or myosin light chain phosphorylation or applying IL-17A-neutralizing antibodies prevented IL-17A-induced BBB disruption. Treatment of mice with EAE using ML-7, an inhibitor of the myosin light chain kinase, resulted in less BBB disruption at the spinal cord and less infiltration of lymphocytes via the BBB and subsequently reduced the clinical characteristics of EAE. These observations indicate that IL-17A accounts for a crucial step in the development of EAE by impairing the integrity of the BBB, involving augmented production of ROS.-Huppert, J., Closhen, D., Croxford, A., White, R., Kulig, P., Pietrowski, E., Bechmann, I., Becher, B., Luhmann, H. J., Waisman, A., Kuhlmann, C. R. W. Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Experimental Immunology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:April 2010
Deposited On:12 Feb 2010 09:33
Last Modified:14 Dec 2013 20:51
Publisher:Federation of American Societies for Experimental Biology
ISSN:0892-6638
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1096/fj.09-141978
PubMed ID:19940258
Citations:Web of Science®. Times Cited: 80
Google Scholar™
Scopus®. Citation Count: 82

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