The mechanisms underlie the warmth-evoked itch in atopic dermatitis (AD) have not been fully elucidated. Among the temperature-sensitive transient receptor potential (TRP) channels, TRPV3 is activated by innocuous warmth and expressed abundantly in keratinocytes (KCs), where it may play a key role in itch as illustrated by TRPV3 channelopathy, Olmsted syndrome. In this study, we investigated the relation between TRPV3 and warmth-evoked itch in AD. Here, we found a marked upregulation of TRPV3 in AD-lesional skin compared with healthy skin or lesional skin of psoriasis or allergic contact dermatitis. Higher TRPV3 protein level was found in KCs isolated from AD patients (AD KCs) compared to KCs from healthy controls (HC KCs). Upon stimulation with TRPV3 agonist cocktails (2-APB and carvacrol), intracellular Ca2+ increase in AD KCs was significantly higher than that in HC KCs. Modest heat simulation at 33 or 39°C led to a greater release of TSLP, NGF, and PGE2 from AD KCs compared with that observed at room temperature or HC KCs, and silencing of TRPV3 of AD KCs abolished the heat-induced release of these pruritogens. Chemical agonists also triggered the production of abovementioned pruritogens in normal human KCs in TRPV3 depended manner. In addition, TRPV3 was upregulated in the skin of oxazolone (Ox)-challenged AD-like chronic dermatitis mice (Ox-AD mice). Epidermal sheets obtained from Ox-AD mice showed increased release of TSLP and NGF in response to heat and administration of TRPV3 antagonists, 17(R)-resolvin D1 or DPTHF, significantly attenuated their response to heat. Heat-evoked scratching behaviors were also attenuated by TRPV3 antagonists. Our results suggest that enhanced activation of TRPV3 in KCs may contribute to warmth-evoked pruritogens release and itch behaviors in AD.

TRPV3 is highly activated in keratinocytes from patients with atopic dermatitis and contributes to warmth-evoked pruritogens release and itch behaviors