Journal
NATURE MEDICINE
Volume 19, Issue 9, Pages 1161-1165Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3303
Keywords
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Funding
- Deutsche Forschungsgemeinschaft [SFB TR128, TP B1, TP B6, SFB 1009, TP A3, FOR1086, TP2, ME3283/2-1, SFB688 TP A13]
- Bundesministerium fur Bildung und Forschung (Kompetenznetzwerk Multiple Sclerosis) [01G10907, 01DJ12103]
- Else-Kroner-Fresenius Stiftung
- Interdisciplinary Center for Clinical Research (IZKF) Munster [SEED 03/12]
- excellence cluster 'Cells in motion' (CIM)
- CNRS
- LabEx Ionic channel Science and Therapeutics
- Agence Nationale de la Recherche-ANR Emergence [ANR-11-EMMA]
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The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet(1). Circulating blood cells, such as leukocytes, complete the NVU2. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown(3). We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)(35-55) peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid alpha-linolenic acid). These beneficial effects were reduced in Kcnk2(-/-) mice, suggesting TREK-1 activating compounds may be used therapeutically to treat diseases related to BBB dysfunction.
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