Cellular mechanisms of IL‐17‐induced blood‐brain barrier disruption
Open Access
- 6 November 2009
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 24 (4), 1023-1034
- https://doi.org/10.1096/fj.09-141978
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 mono-cyte adhesion and transendothelial migration assays were performed. Experimental autoimmune encephzalomyelitis (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. FASEB J. 24, 1023–1034 (2010). www.fasebj.orgKeywords
Funding Information
- Deutsche Forschungsgemeinschaft (SFB TR52/C2)
- Boehringer Ingelheim Stiftung
This publication has 39 references indexed in Scilit:
- Mechanisms of C-Reactive Protein-Induced Blood–Brain Barrier DisruptionStroke, 2009
- Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expressionFree Radical Biology & Medicine, 2008
- Protective effects of peroxiredoxin-1 at the injured blood–brain barrierFree Radical Biology & Medicine, 2008
- Transcriptomic Screening of Microvascular Endothelial Cells Implicates Novel Molecular Regulators of Vascular Dysfunction after Spinal Cord InjuryJournal of Cerebral Blood Flow & Metabolism, 2008
- Interleukin-17 Production in Central Nervous System-Infiltrating T Cells and Glial Cells Is Associated with Active Disease in Multiple SclerosisThe American Journal of Pathology, 2008
- Activation of protein tyrosine kinases and matrix metalloproteinases causes blood‐brain barrier injury: Novel mechanism for neurodegeneration associated with alcohol abuseGlia, 2007
- TH-17 cells in the circle of immunity and autoimmunityNature Immunology, 2007
- Adhesion and migration of polymorphonuclear leukocytes across human brain microvessel endothelial cells are differentially regulated by endothelial cell adhesion molecules and modulate monolayer permeabilityJournal of Neuroimmunology, 2007
- Tight junction protein expression and barrier properties of immortalized mouse brain microvessel endothelial cellsBrain Research, 2007
- IL-23 is essential for T cell–mediated colitis and promotes inflammation via IL-17 and IL-6JCI Insight, 2006