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Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS

Abstract

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 feet1. Circulating blood cells, such as leukocytes, complete the NVU2. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown3. 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.

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Figure 1: TREK1 inhibition or deletion facilitates lymphocyte migration into the CNS and worsens autoimmune CNS inflammation.
Figure 2: TREK1 deficiency leads to upregulation of cellular adhesion molecules and enhances immune-cell infiltration into the CNS in vivo.
Figure 3: TREK1 deficiency has no effect on intracellular potassium homeostasis but decreases intracellular ERK1/2 phosphorylation and impairs the assembly of the actin cytoskeleton in MBMECs.
Figure 4: A linseed oil–rich diet, which activates TREK1, reduces EAE scores, and TREK1 is downregulated in individuals with multiple sclerosis.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (SFB TR128, TP B1 to H.W., SFB TR128, TP B6 to S.G.M., T.B. and H.-C.P.; SFB 1009, TP A3 to H.W.; FOR1086, TP2 to T.B. and S.G.M.; ME3283/2-1 to S.G.M.; and SFB688 TP A13 to C.K.), the Bundesministerium für Bildung und Forschung (Kompetenznetzwerk Multiple Sclerosis, 01GI0907 to H.W. and 01DJ12103 to T.B. and S.G.M.), the Else-Kröner-Fresenius Stiftung (C.K., S.G.M. and S.B.), the Interdisciplinary Center for Clinical Research (IZKF) Münster (SEED 03/12 to S.B.), the excellence cluster 'Cells in motion' (CIM, to S.G.M., H.W., S.B., T.B. and H.-C.P.), the CNRS and the LabEx Ionic channel Science and Therapeutics (M.B. and C.H.) and the Agence Nationale de la Recherche–ANR Emergence (ANR-11-EMMA to H.M.o.M.). We thank B. Reuter, E. Nass and J. Budde for excellent technical assistance and the UK Multiple Sclerosis Tissue Bank (R. Reynolds) for human brain tissue. The endothelial cell line bEND.5 was a kind gift from D. Vestweber (Max Planck Institute for Molecular Biomedicine).

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S.B. and S.G.M. conceived the study and designed the experiments. S.B. and T.R. performed the main experimental work and analyzed the data. M.K.S., N.B., A.M.H., F.L., P.E., H.M.o.M., T.B. and K.G. performed additional experiments. M.B. and C.H. provided Kcnk2−/− mice and spadin and supervised these experiments. D.S. and B.N. generated bone marrow chimeras. T.B., S.G.M. and H.-C.P. supervised the electrophysiologic experiments and analyzed the data. H.-J.G. supervised the TER experiments. S.B. and T.R. drafted the manuscript, and C.K., H.W. and S.G.M. extensively revised the manuscript and funded the study. All authors provided input throughout the process.

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Correspondence to Stefan Bittner or Sven G Meuth.

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Bittner, S., Ruck, T., Schuhmann, M. et al. Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS. Nat Med 19, 1161–1165 (2013). https://doi.org/10.1038/nm.3303

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