Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS.
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. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. 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-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). 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 α-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.
1] Department of Neurology, University of Münster, Münster, Germany. [2].
Stefan
S
Bittner
Tobias
T
Ruck
Michael K
MK
Schuhmann
Alexander M
AM
Herrmann
Hamid
H
Moha ou Maati
Nicole
N
Bobak
Kerstin
K
Göbel
Friederike
F
Langhauser
David
D
Stegner
Petra
P
Ehling
Marc
M
Borsotto
Hans-Christian
HC
Pape
Bernhard
B
Nieswandt
Christoph
C
Kleinschnitz
Catherine
C
Heurteaux
Hans-Joachim
HJ
Galla
Thomas
T
Budde
Heinz
H
Wiendl
Sven G
SG
Meuth
D000199:Actins / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism*; D001921:Brain / Q000276:immunology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology; D007962:Leukocytes / Q000378:metabolism; D008043:Linseed Oil / Q000008:administration & dosage; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*; D019782:Riluzole / Q000494:pharmacology; D057705:Transendothelial and Transepithelial Migration
D000199:Actins; D000927:Anticonvulsants; D015815:Cell Adhesion Molecules; C090509:Icam1 protein, mouse; D016898:Interferon-alpha; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D024683:Potassium Channels, Tandem Pore Domain; C445081:myelin oligodendrocyte glycoprotein (35-55); C103742:potassium channel protein TREK-1; D018799:Intercellular Adhesion Molecule-1; D019782:Riluzole; D008043:Linseed Oil