Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Medicine volume 19, pages 1161–1165 (2013)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

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.

Similar content being viewed by others

References

  1. Neuwelt, E.A. et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat. Rev. Neurosci. 12, 169–182 (2011).

    Article  CAS  Google Scholar 

  2. Holman, D.W., Klein, R.S. & Ransohoff, R.M. The blood-brain barrier, chemokines and multiple sclerosis. Biochim. Biophys. Acta 1812, 220–230 (2011).

    Article  CAS  Google Scholar 

  3. Weiss, N., Miller, F., Cazaubon, S. & Couraud, P.O. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim. Biophys. Acta 1788, 842–857 (2009).

    Article  CAS  Google Scholar 

  4. Overington, J.P., Al-Lazikani, B. & Hopkins, A.L. How many drug targets are there? Nat. Rev. Drug Discov. 5, 993–996 (2006).

    Article  CAS  Google Scholar 

  5. Honoré, E. The neuronal background K2P channels: focus on TREK1. Nat. Rev. Neurosci. 8, 251–261 (2007).

    Article  Google Scholar 

  6. Heurteaux, C. et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat. Neurosci. 9, 1134–1141 (2006).

    Article  CAS  Google Scholar 

  7. Alloui, A. et al. TREK-1, a K+ channel involved in polymodal pain perception. EMBO J. 25, 2368–2376 (2006).

    Article  CAS  Google Scholar 

  8. Heurteaux, C., Laigle, C., Blondeau, N., Jarretou, G. & Lazdunski, M. α-linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia. Neuroscience 137, 241–251 (2006).

    Article  CAS  Google Scholar 

  9. Mazella, J. et al. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol. 8, e1000355 (2010).

    Article  Google Scholar 

  10. Wang, Q. & Doerschuk, C.M. The signaling pathways induced by neutrophil-endothelial cell adhesion. Antioxid. Redox Signal. 4, 39–47 (2002).

    Article  CAS  Google Scholar 

  11. Garry, A. et al. Altered acetylcholine, bradykinin and cutaneous pressure–induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link. EMBO Rep. 8, 354–359 (2007).

    Article  CAS  Google Scholar 

  12. Namiranian, K. et al. Cerebrovascular responses in mice deficient in the potassium channel, TREK-1. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R461–R469 (2010).

    Article  CAS  Google Scholar 

  13. Duprat, F. et al. The neuroprotective agent riluzole activates the two P domain K+ channels TREK-1 and TRAAK. Mol. Pharmacol. 57, 906–912 (2000).

    CAS  PubMed  Google Scholar 

  14. Gilgun-Sherki, Y., Panet, H., Melamed, E. & Offen, D. Riluzole suppresses experimental autoimmune encephalomyelitis: implications for the treatment of multiple sclerosis. Brain Res. 989, 196–204 (2003).

    Article  CAS  Google Scholar 

  15. Nordøy, A. Dietary fatty acids and coronary heart disease. Lipids 34 (suppl.), S19–S22 (1999).

    Article  Google Scholar 

  16. Lauritzen, I. et al. Polyunsaturated fatty acids are potent neuroprotectors. EMBO J. 19, 1784–1793 (2000).

    Article  CAS  Google Scholar 

  17. Nguemeni, C. et al. Dietary supplementation of α-linolenic acid in an enriched rapeseed oil diet protects from stroke. Pharmacol. Res. 61, 226–233 (2010).

    Article  CAS  Google Scholar 

  18. Lauritzen, I. et al. Cross-talk between the mechano-gated K2P channel TREK-1 and the actin cytoskeleton. EMBO Rep. 6, 642–648 (2005).

    Article  CAS  Google Scholar 

  19. Heurteaux, C. et al. TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J. 23, 2684–2695 (2004).

    Article  CAS  Google Scholar 

  20. Bittner, S. et al. TASK1 modulates inflammation and neurodegeneration in autoimmune inflammation of the central nervous system. Brain 132, 2501–2516 (2009).

    Article  Google Scholar 

  21. Schneider-Hohendorf, T. et al. Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis. Eur. J. Immunol. 40, 3581–3590 (2010).

    Article  CAS  Google Scholar 

  22. Göbel, K. et al. Blockade of the kinin receptor B1 protects from autoimmune CNS disease by reducing leukocyte trafficking. J. Autoimmun. 36, 106–114 (2011).

    Article  Google Scholar 

  23. Huang, Y.H. et al. Specific central nervous system recruitment of HLA-G+ regulatory T cells in multiple sclerosis. Ann. Neurol. 66, 171–183 (2009).

    Article  CAS  Google Scholar 

  24. Kleinewietfeld, M. et al. CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset. Blood 105, 2877–2886 (2005).

    Article  CAS  Google Scholar 

  25. Schuhmann, M.K. et al. Stromal interaction molecules 1 and 2 are key regulators of autoreactive T cell activation in murine autoimmune central nervous system inflammation. J. Immunol. 184, 1536–1542 (2010).

    Article  CAS  Google Scholar 

  26. Bittner, S. et al. Upregulation of K2P5.1 potassium channels in multiple sclerosis. Ann. Neurol. 68, 58–69 (2010).

    Article  CAS  Google Scholar 

  27. Dodt, H.U. & Zieglgansberger, W. Visualizing unstained neurons in living brain slices by infrared DIC-videomicroscopy. Brain Res. 537, 333–336 (1990).

    Article  CAS  Google Scholar 

  28. Moha ou Maati, H. et al. A human TREK-1/HEK cell line: a highly efficient screening tool for drug development in neurological diseases. PLoS ONE 6, e25602 (2011).

    Article  CAS  Google Scholar 

  29. Duprat, F. et al. The neuroprotective agent riluzole activates the two P-domain K+ channels TREK-1 and TRAAK. Mol. Pharmacol. 57, 906–912 (2000).

    CAS  PubMed  Google Scholar 

  30. Moha ou Maati, H. et al. Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology 62, 278–288 (2011).

    Article  Google Scholar 

  31. De Bock, M. et al. Low extracellular Ca2+ conditions induce an increase in brain endothelial permeability that involves intercellular Ca2+ waves. Brain Res. 1487, 78–87 (2012).

    Article  CAS  Google Scholar 

  32. Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003).

    Article  CAS  Google Scholar 

  33. Krishnamoorthy, G., Holz, A. & Wekerle, H. Experimental models of spontaneous autoimmune disease in the central nervous system. J. Mol. Med. (Berl) 85, 1161–1173 (2007).

    Article  CAS  Google Scholar 

  34. Williams, J.L. et al. Memory cells specific for myelin oligodendrocyte glycoprotein (MOG) govern the transfer of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 234, 84–92 (2011).

    Article  CAS  Google Scholar 

  35. Dixon, W. & Massey, F. Introduction to Statistical Analysis (McGraw-Hill Companies, New York, 1969).

Download references

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).

Author information

Author notes

  1. Stefan Bittner, Tobias Ruck, Heinz Wiendl and Sven G Meuth: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, University of Münster, Münster, Germany

    Stefan Bittner, Tobias Ruck, Michael K Schuhmann, Alexander M Herrmann, Nicole Bobak, Kerstin Göbel, Petra Ehling, Heinz Wiendl & Sven G Meuth

  2. Department of Neurology, University of Würzburg, Würzburg, Germany

    Michael K Schuhmann, Friederike Langhauser, David Stegner & Christoph Kleinschnitz

  3. Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, Valbonne, France

    Hamid Moha ou Maati, Marc Borsotto & Catherine Heurteaux

  4. Chair of Vascular Medicine, University Hospital Würzburg and Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany

    David Stegner & Bernhard Nieswandt

  5. Institute of Physiology I–Neuropathophysiology, University of Münster, Münster, Germany

    Petra Ehling & Sven G Meuth

  6. Institute of Physiology I, University of Münster, Münster, Germany

    Hans-Christian Pape & Thomas Budde

  7. Institute of Biochemistry, University of Münster, Münster, Germany

    Hans-Joachim Galla

Authors
  1. Stefan Bittner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tobias Ruck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael K Schuhmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander M Herrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hamid Moha ou Maati
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicole Bobak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kerstin Göbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Friederike Langhauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David Stegner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Petra Ehling
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marc Borsotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hans-Christian Pape
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Bernhard Nieswandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Christoph Kleinschnitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Catherine Heurteaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hans-Joachim Galla
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Thomas Budde
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Heinz Wiendl
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Sven G Meuth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Stefan Bittner or Sven G Meuth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–15 (PDF 1845 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3303

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing