Transient receptor potential vanilloid 2 functions as a directional driver for hepoxilin A₃-mediated neutrophil...

Neutrophil migration involves a dynamic balance of chemoattractant and inhibitory signals. We previously identified hepoxilin A₃ (HxA₃) as a potent chemoattractant that directs neutrophil migration across intestinal epithelia and showed that endocannabinoids can suppress migration through the cannabinoid 2 receptor (CB₂R). Here, we reveal that HxA₃ uses the transient receptor potential vanilloid type 2 (TRPV2) cation channel to promote transmigration, a process finely tuned by physical TRPV2-CB₂R interaction. In resting neutrophils, surface-localized CB₂R responding to endocannabinoids suppresses migration, while a small fraction of TRPV2 at the plasma membrane "senses" HxA₃. HxA₃ drives the movement of an intracellular "storage" pool of TRPV2 to the leading edge of migration where physical interaction with CB₂R establishes cell surface receptor complexes to direct neutrophil migration. Postactivation, TRPV2 is shunted toward degradation, while CB₂R is both replaced and recycled to the plasma membrane to establish a coordinated system capable of maintaining directional fidelity to HxA₃ gradients. These findings uncover a previously unrecognized layer of neutrophil trafficking regulation.