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

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.