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

FASEB J. 2010 Apr;24(4):1023-34. doi: 10.1096/fj.09-141978. Epub 2009 Nov 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology
  • Azepines / pharmacology
  • Blood-Brain Barrier / immunology
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Cell Line, Transformed
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Enzyme Inhibitors / pharmacology
  • Interleukin-17 / antagonists & inhibitors
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • Interleukin-17 / pharmacology
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Myosin-Light-Chain Kinase
  • NADPH Oxidases / immunology
  • NADPH Oxidases / metabolism
  • Naphthalenes / pharmacology
  • Occludin
  • Oxidative Stress / drug effects
  • Oxidative Stress / immunology
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism*
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • T-Lymphocytes, Helper-Inducer / pathology
  • Xanthine Oxidase / immunology
  • Xanthine Oxidase / metabolism


  • Antibodies, Neutralizing
  • Azepines
  • Enzyme Inhibitors
  • Il17a protein, mouse
  • Interleukin-17
  • Membrane Proteins
  • Naphthalenes
  • Occludin
  • Ocln protein, mouse
  • Reactive Oxygen Species
  • ML 7
  • Xanthine Oxidase
  • NADPH Oxidases
  • Myosin-Light-Chain Kinase