Article

Cellular mechanisms of IL-17-induced blood-brain barrier disruption.

University Medical Center of the Johannes Gutenberg University Mainz, Institute of Physiology and Pathophysiology, Duesbergweg 6, 55131 Mainz, Germany.
The FASEB Journal (impact factor: 5.71). 11/2009; 24(4):1023-34. DOI:10.1096/fj.09-141978 pp.1023-34
Source: PubMed

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.

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Keywords

applying IL-17A-neutralizing antibodies
 
Barrier integrity
 
blood-brain barrier
 
clinical characteristics
 
electrical call impedance
 
electrical resistance values
 
Experimental autoimmune encephalomyelitis
 
fluorescence imaging
 
IL-17-induced blood-brain barrier disruption
 
IL-17A accounts
 
IL-17A induced NADPH oxidase-
 
IL-17A-induced BBB disruption
 
in-cell Western blots
 
junction molecule occludin
 
myosin light chain kinase
 
myosin light chain phosphorylation
 
resulting oxidative stress activated
 
T-helper 17
 
transendothelial migration assays
 
underlie IL-17A-induced BBB breakdown