Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary; Department of Medical Biology, University of Pécs Medical School, Pécs, Hungary; János Szentágothai Research Center, University of Pécs, Pécs, Hungary.
Vascular Biology and Inflammation Section, BHF Centre of Cardiovascular Excellence, King's College London, London, UK.
J Invest Dermatol. 2018 Aug;138(8):1774-1784. doi: 10.1016/j.jid.2018.02.040. Epub 2018 Mar 14.
This study revealed the modulatory role of transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) cation channels in the Aldara-induced (5% imiquimod) murine psoriasis model using selective antagonists and genetically altered animals. We have also developed a refined localized model to enable internal controls and reduce systemic effects. Skin pathology was quantified by measuring skin thickness, scaling, blood flow, and analyzing dermal cellular infiltrate, whereas nocifensive behaviors were also observed. Cytokine gene expression profiles were measured ex vivo. Psoriasiform dermatitis was significantly enhanced in TRPA1 knockout mice and with TRPA1 antagonist (A967079) treatment. By comparison, symptoms were decreased when TRPV1 function was inhibited. Imiquimod induced Ca influx in TRPA1-, but not in TRPV1-expressing cell lines. Immunohistochemical studies revealed that CD4+ T helper cells express TRPA1 but not TRPV1 ion channels in mice skin. Compared with the TRPV1 knockout animals, additional elimination of the TRPA1 channels in the TRPV1/TRPA1 double knockout mice did not modify the outcome of the imiquimod-induced reaction, further supporting the dominant role of TRPV1 in the process. Our results suggest that the protective effects in psoriasiform dermatitis can be mediated by the activation of neuronal and nonneuronal TRPA1 receptors.
本研究利用选择性拮抗剂和基因改造动物，揭示了瞬时受体电位锚蛋白 1（TRPA1）和香草素 1（TRPV1）阳离子通道在 Aldara（5%咪喹莫特）诱导的小鼠银屑病模型中的调节作用。我们还开发了一种改良的局部模型，以实现内部对照并减少全身效应。通过测量皮肤厚度、脱屑、血流量和分析真皮细胞浸润，以及观察伤害性行为来量化皮肤病理学。还测量了细胞因子基因表达谱。TRPA1 基因敲除小鼠和 TRPA1 拮抗剂（A967079）治疗组的银屑病样皮炎明显加重，而 TRPV1 功能受到抑制时症状减轻。与 TRPV1 敲除动物相比，在 TRPV1/TRPA1 双基因敲除小鼠中进一步消除 TRPA1 通道并没有改变咪喹莫特诱导反应的结果，进一步支持 TRPV1 在该过程中的主导作用。我们的结果表明，神经元和非神经元 TRPA1 受体的激活可以介导银屑病样皮炎的保护作用。
