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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2024

Open Access 01-12-2024 | Multiple Sclerosis | Research

Inflammation-induced TRPV4 channels exacerbate blood–brain barrier dysfunction in multiple sclerosis

Authors: Cathrin E. Hansen, Alwin Kamermans, Kevin Mol, Kristina Berve, Carla Rodriguez-Mogeda, Wing Ka Fung, Bert van het Hof, Ruud D. Fontijn, Susanne M. A. van der Pol, Laura Michalick, Wolfgang M. Kuebler, Boyd Kenkhuis, Willeke van Roon-Mom, Wolfgang Liedtke, Britta Engelhardt, Gijs Kooij, Maarten E. Witte, Helga E. de Vries

Published in: Journal of Neuroinflammation | Issue 1/2024

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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.
Appendix
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Metadata
Title
Inflammation-induced TRPV4 channels exacerbate blood–brain barrier dysfunction in multiple sclerosis
Authors
Cathrin E. Hansen
Alwin Kamermans
Kevin Mol
Kristina Berve
Carla Rodriguez-Mogeda
Wing Ka Fung
Bert van het Hof
Ruud D. Fontijn
Susanne M. A. van der Pol
Laura Michalick
Wolfgang M. Kuebler
Boyd Kenkhuis
Willeke van Roon-Mom
Wolfgang Liedtke
Britta Engelhardt
Gijs Kooij
Maarten E. Witte
Helga E. de Vries
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-024-03069-9

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