BACKGROUND: Atopic Dermatitis (AD) is a multifaceted inflammatory skin disease characterized by chronic itch and Acute Itch Flare (AIF), with basophils playing pivotal roles in both. While VAMP7 (V7) mediates immune responses, its function in basophils remains undefined. OBJECTIVE: To elucidate the role of V7 in basophil-mediated chronic itch and AIF in AD. METHODS: Basophil-specific V7 knockout (Ba-V7KO) and control V7 RESULTS: Ba-V7KO mice exhibited impaired chronic itch but normal AIF itch, accompanied by reduced skin levels of MCPT8, histamine, CCL24, and CCR3 across both models, while OSM was reduced only in the AIF model. Flow-sorted V7 knockout basophils exhibited reduced activity, with OSM downregulated in AIF and CCR3 reduced in both models. V7 knockout also decreased IL-4 and LTC4 release from basophils. Additionally, OSM upregulated barrier proteins and pruriceptors in keratinocytes
however, these effects were reversed by SC144, which restored skin barrier function in AIF without affecting itch response in either model. In the chronic model, CCR3 inhibition alleviated pruritus, correlating with the downregulation of itch-related transcripts. CONCLUSION: V7 is essential for basophil-driven chronic itch and AIF in AD by: i) maintaining basophil activity, ii) regulating skin barrier damage in AIF via the OSM pathway, and iii) modulating chronic itch through the CCL24/CCR3 axis. Targeting basophil V7 offers a potential strategy to restore skin barrier function in AIF and alleviate chronic itch in AD.