Department of Pharmacology, School of Pharmacy (Y.Q., X.S., K.W.), and Institute of Innovative Drugs (G.W., X.S., K.W.), Qingdao University, Qingdao, China.
Department of Pharmacology, School of Pharmacy (Y.Q., X.S., K.W.), and Institute of Innovative Drugs (G.W., X.S., K.W.), Qingdao University, Qingdao, China
Mol Pharmacol. 2019 Sep;96(3):393-400. doi: 10.1124/mol.119.116962. Epub 2019 Jul 15.
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by cutaneous lesions and intense pruritus. The warm temperature-activated Ca-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)- 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- 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.
特应性皮炎（AD）是一种慢性炎症性皮肤病，其特征为皮肤损伤和剧烈瘙痒。热激活型钙通透性瞬时受体电位香草醛（TRPV）3 通道在角质形成细胞中大量表达，TRPV3 的功能获得性突变可导致啮齿动物和人类出现皮肤损伤和瘙痒，提示 TRPV3 参与 AD 的发病机制。本研究报道 TRPV3 的药理学和遗传学抑制可减轻小鼠的皮肤损伤和皮炎。我们发现，在化学 2,4-二硝基氟苯诱导的 AD 样模型中，TRPV3 蛋白与炎症因子肿瘤坏死因子（TNF）和白细胞介素（IL）-6 一起在小鼠皮肤中上调，通过 Western blot 分析和免疫染色实验检测到这一点。TRPV3 通道激动剂和皮肤敏化剂香芹酚对 TRPV3 的药理学激活导致野生型小鼠而不是 TRPV3 敲除小鼠发生 AD。此外，天然蛇床子素对 TRPV3 的抑制以剂量依赖性方式逆转了炎症性背部皮肤和耳部水肿的严重程度，并降低了炎症因子 TNF 和 IL-6 的表达。总之，这些发现表明过度活跃的 TRPV3 参与了小鼠 AD 的进行性病理过程，TRPV3 通道功能的局部抑制可能是预防和治疗 AD 或炎症性皮肤病的有效选择。
