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

Hansen, Cathrin E; Kamermans, Alwin; Mol, Kevin; Berve, Kristina; Rodriguez-Mogeda, Carla; Fung, Wing Ka; van Het Hof, Bert; Fontijn, Ruud D; van der Pol, Susanne M A; Michalick, Laura; Kuebler, Wolfgang M; Kenkhuis, Boyd; van Roon-Mom, Willeke; Liedtke, Wolfgang; Engelhardt, Britta; Kooij, Gijs; Witte, Maarten E; de Vries, Helga E (2024). Inflammation-induced TRPV4 channels exacerbate blood-brain barrier dysfunction in multiple sclerosis. Journal of neuroinflammation, 21(72) BioMed Central 10.1186/s12974-024-03069-9

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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.

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