Role of SNAREs in the Atopic Dermatitis-related Cytokine Secretion and Skin-Nerve Communication.
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 Ca2+-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.
School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland; Department of Dermatology and UCD Charles Institute for Translational Dermatology, Dublin, Ireland.,
School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland.,
Department of Dermatology and Venereology, and Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; Qatar University, Medical School, Doha, Qatar.,
Department of Dermatology, University Medical Center Göttingen, Göttingen, Germany.
Department of Dermatology and UCD Charles Institute for Translational Dermatology, Dublin, Ireland; Department of Dermatology and Venereology, and Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; Qatar University, Medical School, Doha, Qatar; Weill Cornell Medicine-Qatar, School of Medicine, and Qatar University, Doha, Qatar; Dept. of Dermatology, Weill Cornell University, New York, NY, USA.
Pub Type(s)Journal Article