This study investigates the role of transient receptor potential vanilloid-type 4 (TRPV4) ion channels in blood-brain barrier (BBB) dysfunction in multiple sclerosis (MS). The authors found that TRPV4 expression is regionally increased around mixed active/inactive lesions in MS brain tissue, coinciding with increased perivascular microglia. In vitro experiments revealed that microglia-derived tumor necrosis factor-α (TNFα) induces TRPV4 expression in brain endothelial cells. TRPV4 levels influence BBB formation by regulating claudin-5 expression, a tight junction molecule. During inflammation, TRPV4 promotes a pathological endothelial molecular signature, including enhanced expression of inflammatory mediators and cell adhesion molecules, and facilitates T cell extravasation across the BBB. The findings suggest that enhanced TRPV4 expression in MS contributes to BBB dysfunction and immune cell migration, highlighting TRPV4 as a potential therapeutic target for MS.This study investigates the role of transient receptor potential vanilloid-type 4 (TRPV4) ion channels in blood-brain barrier (BBB) dysfunction in multiple sclerosis (MS). The authors found that TRPV4 expression is regionally increased around mixed active/inactive lesions in MS brain tissue, coinciding with increased perivascular microglia. In vitro experiments revealed that microglia-derived tumor necrosis factor-α (TNFα) induces TRPV4 expression in brain endothelial cells. TRPV4 levels influence BBB formation by regulating claudin-5 expression, a tight junction molecule. During inflammation, TRPV4 promotes a pathological endothelial molecular signature, including enhanced expression of inflammatory mediators and cell adhesion molecules, and facilitates T cell extravasation across the BBB. The findings suggest that enhanced TRPV4 expression in MS contributes to BBB dysfunction and immune cell migration, highlighting TRPV4 as a potential therapeutic target for MS.