Inflammation-induced TRPV4 channels exacerbate blood–brain barrier dysfunction in multiple sclerosis
Journal of Neuroinflammation, vol. 21, pp. 72
Abstract
BACKGROUND: Blood-brain barrier (BBB) dysfunction and immune cell migration into the central nervous system (CNS) are pathogenic drivers of multiple sclerosis (MS). Ways to reinstate BBB function and subsequently limit neuroinflammation present promising strategies to restrict disease progression. However, to date, the molecular players directing BBB impairment in MS remain poorly understood. One suggested candidate to impact BBB function is the transient receptor potential vanilloid-type 4 ion channel (TRPV4), but its specific role in MS pathogenesis remains unclear. Here, we investigated the role of TRPV4 in BBB dysfunction in MS. MAIN TEXT: In human post-mortem MS brain tissue, we observed a region-specific increase in endothelial TRPV4 expression around mixed active/inactive lesions, which coincided with perivascular microglia enrichment in the same area. Using in vitro models, we identified that microglia-derived tumor necrosis factor-α (TNFα) induced brain endothelial TRPV4 expression. Also, we found that TRPV4 levels influenced brain endothelial barrier formation via expression of the brain endothelial tight junction molecule claudin-5. In contrast, during an inflammatory insult, TRPV4 promoted a pathological endothelial molecular signature, as evidenced by enhanced expression of inflammatory mediators and cell adhesion molecules. Moreover, TRPV4 activity mediated T cell extravasation across the brain endothelium. CONCLUSION: Collectively, our findings suggest a novel role for endothelial TRPV4 in MS, in which enhanced expression contributes to MS pathogenesis by driving BBB dysfunction and immune cell migration.
Authors 18
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Cathrin Elly Hansen corresponding
Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands. c.e.hansen@amsterdamumc.nl
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands. c.e.hansen@amsterdamumc.nl
MS Center Amsterdam, Amsterdam UMC Location VU Medical Center, Amsterdam, The Netherlands. c.e.hansen@amsterdamumc.nl
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
MS Center Amsterdam, Amsterdam UMC Location VU Medical Center, Amsterdam, The Netherlands
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Amsterdam UMC Location University of Amsterdam
Affiliation as printed
Department of Biomedical Engineering and Physics, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
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Affiliation as printed
Theodor Kocher Institute, University of Bern, Bern, Switzerland
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
MS Center Amsterdam, Amsterdam UMC Location VU Medical Center, Amsterdam, The Netherlands
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
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German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
Institute of Physiology, Corporate member of the Freie Universität Berlin and Humboldt Universität to Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
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St. Michael's Hospital · University of Toronto · German Centre for Cardiovascular Research · Freie Universität Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
Departments of Surgery and Physiology, University of Toronto, Toronto, ON, Canada
Institute of Physiology, Corporate member of the Freie Universität Berlin and Humboldt Universität to Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada
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Leiden University Medical Center · University of Edinburgh
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands
UK Dementia Research Institute at University of Edinburgh, Edinburgh, UK
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands
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Duke University · New York University
Affiliation as printed
Department of Molecular Pathobiology, New York University College of Dentistry, New York, USA
Department of Neurology, Duke University, Durham, NY, USA
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Affiliation as printed
Theodor Kocher Institute, University of Bern, Bern, Switzerland
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam UMC, Amsterdam, The Netherlands
Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
MS Center Amsterdam, Amsterdam UMC Location VU Medical Center, Amsterdam, The Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam UMC, Amsterdam, The Netherlands
Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
MS Center Amsterdam, Amsterdam UMC Location VU Medical Center, Amsterdam, The Netherlands
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Helga E. de Vries corresponding
Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, The Netherlands. he.devries@amsterdamumc.nl
Department of Molecular Cell Biology and Immunology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands. he.devries@amsterdamumc.nl
MS Center Amsterdam, Amsterdam UMC Location VU Medical Center, Amsterdam, The Netherlands. he.devries@amsterdamumc.nl
MS Center Amsterdam, Amsterdam UMC Location VU Medical Center, Amsterdam, The Netherlands
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