Papers of the Week

The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in atopic dermatitis (AD) is unknown. This study is envisioned to lead to the previously unreported SNARE function in AD-related cytokine secretion and epidermis-nerve communication. Herein, we report that various cytokines were simultaneously upregulated and co-released in the innate immunity-activated primary human keratinocytes (phKCs). AD-related cytokines thymic stromal lymphopoietin (TSLP), endothelin-1 (ET-1) or inflammatory TNF-α activated distinct but overlapping sensory neurons. Interestingly, TNF-α potentiated TSLP-induced Ca-influx, whereas ET-1 caused itch-selective B-type natriuretic peptide (BNP) release. In phKCs, BNP upregulated genes promoting dermatological and neuroinflammatory diseases and conditions. VAMP3, SNAP-29 and syntaxin4 proved important in driving cytokine release from phKCs. Depletion of VAMP3 inhibited nearly all the cytokine release including TSLP and ET-1. Accordingly, VAMP3 co-occurred with ET-1 in AD patient skin. Our study pinpoints the pivotal role of SNAREs in mediating cytokine secretion related to AD. VAMP3 is identified as a suitable target for developing broad-spectrum anti-cytokine therapeutics for controlling itch and atopic skin inflammation.