Transient receptor potential vanilloid 2 functions as a directional driver for hepoxilin A ₃ –mediated neutrophil migration

Neutrophil migration involves a dynamic balance of chemoattractant and inhibitory signals. We previously identified hepoxilin A 3 (HxA 3 ) as a potent chemoattractant that directs neutrophil migration across intestinal epithelia and showed that endocannabinoids can suppress migration through the cannabinoid 2 receptor (CB 2 R). Here, we reveal that HxA 3 uses the transient receptor potential vanilloid type 2 (TRPV2) cation channel to promote transmigration, a process finely tuned by physical TRPV2-CB 2 R interaction. In resting neutrophils, surface-localized CB 2 R responding to endocannabinoids suppresses migration, while a small fraction of TRPV2 at the plasma membrane “senses” HxA 3 . HxA 3 drives the movement of an intracellular “storage” pool of TRPV2 to the leading edge of migration where physical interaction with CB 2 R establishes cell surface receptor complexes to direct neutrophil migration. Postactivation, TRPV2 is shunted toward degradation, while CB 2 R is both replaced and recycled to the plasma membrane to establish a coordinated system capable of maintaining directional fidelity to HxA 3 gradients. These findings uncover a previously unrecognized layer of neutrophil trafficking regulation.