Role of SNAREs in Atopic Dermatitis–Related Cytokine Secretion and Skin-Nerve Communication

Abstract

The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors in atopic dermatitis (AD) is unknown. This study identifies the function of soluble N-ethylmaleimide sensitive factor attachment protein receptor in AD-related cytokine secretion and epidermis-nerve communication. Herein, we report that various cytokines were simultaneously upregulated and coreleased in innate immunityeactivated primary human keratinocytes. AD-related cytokines thymic stromal lymphopoietin, endothelin-1, and inflammatory tumor necrosis factor-a activated distinct but overlapping sensory neurons. Tumor necrosis factor-a potentiated thymic stromal lymphopoietineinduced Ca 2þ-influx, whereas endothelin-1 caused itch-selective B-type natriuretic peptide release. In primary human keratinocytes, B-type natriuretic peptide upregulated genes promoting dermatological and neuroinflammatory diseases and conditions. VAMP3, SNAP-29, and syntaxin 4 proved important in driving cytokine release from primary human keratinocytes. Depletion of VAMP3 inhibited nearly all the cytokine release including thymic stromal lymphopoietin and endothelin-1. Accordingly, VAMP3 co-occurred with endothelin-1 in the skins of patients with AD. Our study pinpoints the pivotal role of soluble N-ethylmaleimide sensitive factor attachment protein receptors in mediating cytokine secretion related to AD. VAMP3 is identified as a suitable target for developing broad-spectrum anticytokine therapeutics for controlling itch and atopic skin inflammation.

Interventions in the B‐type natriuretic peptide signalling pathway as a means of controlling chronic itch

“…In primary human keratinocytes (phKCs), several key intracellular phospho‐kinases were activated by BNP, and this elicited several cytokines (Figure b), involved in itchy skin (Meng et al, ). The effect of BNP in skin cells is closely correlated with dermatological diseases and conditions (Meng, Wang, Buddenkotte, Buhl, & Steinhoff, ). To reveal the connections between the shared differentially regulated genes (Figure a), we constructed the biomolecular networks in BNP‐activated phKCs (Figure b), and the established and putative interactions of cytokines were shown using IPA analysis (Figure b).…”

“…Hot and cold coloured genes are up‐ and down‐regulated respectively. Transcriptome experiments and analysis was carried as described in Meng et al (). IPA analysis was performed using QIAGEN's Ingenuity Pathway Analysis (QIAGEN Bioinformatics) software [Colour figure can be viewed at wileyonlinelibrary.com]…”

“…IL‐31 and endothelin 1 (ET‐1) released from Th2 cells initiate a closed itch circuit between sensory neurons and skin cells, as well as immune cells, through BNP. Thus, BNP acts as an itch relay centre (Meng et al, ; Meng et al, ). In addition, BNP further augments AD‐related cytokine release from skin cells, through its specific receptors elevated or activated in diseased epidermal skin.…”

“…For targeting purposes, one of the interesting findings is that the synthesis and release of BNP from pruritic sensory neurons differ from other neurotransmitters, such as substance P and CGRP. Release of BNP could be elicited by IL‐31 (Meng et al, ; Pitake et al, ) and ET‐1 (Meng et al, ), the key itch mediators that play important roles in the pathogenesis of AD. In contrast, IL‐31 did not elicit synthesis and release of CGRP or substance P. The enhanced BNP release, but not its resting level, from pruritic sensory neurons requires a particular exocytotic process involving the soluble N‐ethylmaleimide‐sensitive factor activating protein receptor (SNARE) (Meng & Wang, ).…”

“…These exocytotic proteins might serve as promising targets for blocking BNP‐mediated itch (Figure b). In addition, different SNARE isoforms also regulate the release of ET‐1, thymic stromal lymphopoietin, and many other itch‐related cytokine/chemokines, from skin cells that play important roles in immune‐neuron communication (Meng et al, ; Figure b). Thus, targeting these SNARE proteins should break the crosstalk link between sensory neurons and skin cells.…”