PDF(Pubmed)
Abstract：
Semaphorin 3A (SEMA3A), a nerve-repellent factor produced by keratinocytes, has an inhibitory effect on nerve extension to the epidermis. Epidermal innervation is involved in pruritus in inflammatory skin diseases such as atopic dermatitis (AD) and dry skin. We previously reported that tapinarof, a stilbene molecule, upregulates SEMA3A in human keratinocytes. We also showed that this mechanism is mediated via the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and the nuclear factor erythroid 2-related factor 2 (NRF2) axis. Since some stilbenes activate AHR and NRF2, we attempted to identify other stilbenes that upregulate SEMA3A. We analyzed normal human epidermal keratinocytes (NHEKs) treated with 11 types of stilbenes and examined SEMA3A expression. We found that resveratrol and pinostilbene, antioxidant polyphenols, upregulated SEMA3A and increased nuclear AHR and NRF2 expression. In addition, AHR knockdown by small interfering RNA (siRNA) transfection abolished the NRF2 nuclear expression. Furthermore, AHR and NRF2 knockdown by siRNA transfection abrogated resveratrol- and pinostilbene-induced SEMA3A upregulation. Finally, we confirmed that resveratrol and pinostilbene increased SEMA3A promoter activity through NRF2 binding using ChIP-qPCR analysis. These results suggest that resveratrol and pinostilbene upregulate SEMA3A via the AHR-NRF2 axis in human keratinocytes.
摘要：
信号3A（SEMA3A），角质形成细胞产生的神经排斥因子，对神经延伸到表皮有抑制作用。表皮神经支配涉及炎性皮肤病如特应性皮炎(AD)和干性皮肤的瘙痒。我们之前报道过tapinarof,一种二苯乙烯分子,在人角质形成细胞中上调SEMA3A。我们还表明，这种机制是通过芳烃受体（AHR）介导的，配体激活的转录因子，和核因子红系2相关因子2（NRF2）轴。由于一些二苯乙烯激活AHR和NRF2,我们试图鉴定上调SEMA3A的其他二苯乙烯。我们分析了用11种二苯乙烯处理的正常人表皮角质形成细胞（NHEK），并检查了SEMA3A的表达。我们发现白藜芦醇和匹诺二苯乙烯,抗氧化剂多酚，上调SEMA3A并增加核AHR和NRF2表达。此外,通过小干扰RNA(siRNA)转染的AHR敲除消除了NRF2核表达。此外，通过siRNA转染的AHR和NRF2敲低消除了白藜芦醇和pinostilbene诱导的SEMA3A上调。最后,我们使用ChIP-qPCR分析证实白藜芦醇和pinostilbene通过NRF2结合增加SEMA3A启动子活性。这些结果表明白藜芦醇和松二苯乙烯通过人角质形成细胞中的AHR-NRF2轴上调SEMA3A。
