Inhibition of the Warm Temperature-Activated Ca2+-Permeable Transient Receptor Potential Vanilloid TRPV3 Channel Attenuates Atopic Dermatitis.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by cutaneous lesions and intense pruritus. The warm temperature-activated Ca2+-permeable transient receptor potential vanilloid (TRPV)3 channel is abundantly expressed in keratinocytes, and gain-of-function mutations of TRPV3 cause skin lesions and pruritus in rodents and humans, suggesting an involvement of TRPV3 in the pathogenesis of AD. Here we report that pharmacological and genetic inhibition of TRPV3 attenuates skin lesions and dermatitis in mice. We found that TRPV3 proteins, together with inflammatory factors tumor necrosis factor (TNF)-α and interleukin (IL)-6, were upregulated in the skin of mice in a AD-like model induced by topical application of chemical 2,4-dinitrofluorobenzene, as detected by Western blot analysis and immunostaining assays. Pharmacological activation of TRPV3 by channel agonist and skin sensitizer carvacrol resulted in the development of AD in wild-type mice but not in TRPV3 knockout mice. Furthermore, inhibition of TRPV3 by natural osthole reversed the severity of inflammatory dorsal skin and ear edema in a dose-dependent manner and also decreased expression of inflammatory factors TNF-α and IL-6. Taken together, our findings demonstrate the involvement of overactive TRPV3 in the progressive pathology of AD in mice, and topical inhibition of TRPV3 channel function may represent an effective option for preventing and treating AD or inflammatory skin diseases. SIGNIFICANCE STATEMENT: The overactive transient receptor potential vanilloid TRPV3 channel is critically involved in the pathogenesis of atopic dermatitis. Inhibition of TRPV3 channel function by topical natural osthole may represent an effective therapy for management of atopic dermatitis aimed at preventing or alleviating skin lesions and severe itching.

• Authors: Yaxuan Qu, Gongxin Wang, Xiaoying Sun, KeWei Wang
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 96 Issue 3 Pg. 393-400 (09 2019) ISSN: 1521-0111 [Electronic] United States
• PMID: 31308264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Coumarins
• Cymenes
• Interleukin-6
• TRPV Cation Channels
• Trpv3 protein, mouse
• Tumor Necrosis Factor-alpha
• interleukin-6, mouse
• carvacrol
• Dinitrofluorobenzene
• osthol

Topics

• Administration, Topical
• Animals
• Coumarins (administration & dosage, pharmacology)
• Cymenes (adverse effects)
• Dermatitis, Atopic (chemically induced, drug therapy, metabolism)
• Dinitrofluorobenzene (adverse effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hot Temperature
• Humans
• Interleukin-6 (metabolism)
• Male
• Mice
• TRPV Cation Channels (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation (drug effects)