PMID- 23933981
OWN - NLM
STAT- MEDLINE
DCOM- 20131125
LR  - 20211021
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Linking)
VI  - 19
IP  - 9
DP  - 2013 Sep
TI  - Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell 
      trafficking into the CNS.
PG  - 1161-5
LID - 10.1038/nm.3303 [doi]
AB  - 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-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.
FAU - Bittner, Stefan
AU  - Bittner S
AD  - 1] Department of Neurology, University of Munster, Munster, Germany. [2].
FAU - Ruck, Tobias
AU  - Ruck T
FAU - Schuhmann, Michael K
AU  - Schuhmann MK
FAU - Herrmann, Alexander M
AU  - Herrmann AM
FAU - Moha ou Maati, Hamid
AU  - Moha ou Maati H
FAU - Bobak, Nicole
AU  - Bobak N
FAU - Gobel, Kerstin
AU  - Gobel K
FAU - Langhauser, Friederike
AU  - Langhauser F
FAU - Stegner, David
AU  - Stegner D
FAU - Ehling, Petra
AU  - Ehling P
FAU - Borsotto, Marc
AU  - Borsotto M
FAU - Pape, Hans-Christian
AU  - Pape HC
FAU - Nieswandt, Bernhard
AU  - Nieswandt B
FAU - Kleinschnitz, Christoph
AU  - Kleinschnitz C
FAU - Heurteaux, Catherine
AU  - Heurteaux C
FAU - Galla, Hans-Joachim
AU  - Galla HJ
FAU - Budde, Thomas
AU  - Budde T
FAU - Wiendl, Heinz
AU  - Wiendl H
FAU - Meuth, Sven G
AU  - Meuth SG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130811
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Actins)
RN  - 0 (Anticonvulsants)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Icam1 protein, mouse)
RN  - 0 (Interferon-alpha)
RN  - 0 (Myelin-Oligodendrocyte Glycoprotein)
RN  - 0 (Peptide Fragments)
RN  - 0 (Potassium Channels, Tandem Pore Domain)
RN  - 0 (myelin oligodendrocyte glycoprotein (35-55))
RN  - 0 (potassium channel protein TREK-1)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - 7LJ087RS6F (Riluzole)
RN  - 8001-26-1 (Linseed Oil)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Anticonvulsants/pharmacology
MH  - Blood-Brain Barrier/immunology/*metabolism
MH  - Brain/immunology/*metabolism
MH  - Cell Adhesion Molecules/biosynthesis/immunology
MH  - Cell Movement
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Dendritic Cells
MH  - Down-Regulation
MH  - Encephalomyelitis, Autoimmune, Experimental/drug therapy/metabolism
MH  - Endothelial Cells/*metabolism
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Intercellular Adhesion Molecule-1/immunology/metabolism
MH  - Interferon-alpha/pharmacology
MH  - Leukocytes/metabolism
MH  - Linseed Oil/administration & dosage
MH  - MAP Kinase Signaling System
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myelin-Oligodendrocyte Glycoprotein
MH  - Peptide Fragments
MH  - Potassium Channels, Tandem Pore Domain/genetics/*metabolism
MH  - Riluzole/pharmacology
MH  - Transendothelial and Transepithelial Migration
EDAT- 2013/08/13 06:00
MHDA- 2013/12/16 06:00
CRDT- 2013/08/13 06:00
PHST- 2013/03/21 00:00 [received]
PHST- 2013/07/16 00:00 [accepted]
PHST- 2013/08/13 06:00 [entrez]
PHST- 2013/08/13 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
AID - nm.3303 [pii]
AID - 10.1038/nm.3303 [doi]
PST - ppublish
SO  - Nat Med. 2013 Sep;19(9):1161-5. doi: 10.1038/nm.3303. Epub 2013 Aug 11.