Basophil-VAMP7 is a vital regulator of skin barrier integrity and chronic itch

Abstract

BackgroundAtopic dermatitis (AD) is a multifaceted inflammatory skin disease characterized by chronic itch and acute itch flare (AIF), with basophils playing pivotal roles in both. VAMP7 mediates immune responses; however, its function in basophils remains undefined. ObjectiveWe sought to elucidate the role of VAMP7 in basophil-mediated chronic itch and AIF in AD. MethodsBasophil-specific VAMP7 knockout (Ba-V7KO) and control V7fl/fl mice were used to model chronic itch and AIF in AD. The role of basophil-VAMP7 was assessed through RNA sequencing, fluorescence-activated cell sorting, quantitative RT-PCR, ELISA, and pharmacological inhibition. ResultsBa-V7KO mice exhibited impaired chronic itch but normal AIF, accompanied by reduced skin levels of MCPT8, histamine, CCL24, and CCR3 across both models, whereas OSM was reduced only in the AIF model. After fluorescence-activated cell sorting, VAMP7 knockout basophils exhibited reduced activity, with OSM downregulated in AIF and CCR3 reduced in both models. VAMP7 knockout also decreased IL-4 and LTC4 release from basophils. Additionally, OSM downregulated barrier proteins and upregulated 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. ConclusionVAMP7 is essential for basophil-driven chronic itch and AIF in AD by maintaining basophil activity, regulating skin barrier damage in AIF via the OSM pathway, and modulating chronic itch through the CCL24/CCR3 axis. Targeting basophil-VAMP7 offers a potential strategy to restore skin barrier function in AIF and alleviate chronic itch in AD.