Environmental factors transmitted by aryl hydrocarbon receptor influence severity of psoriatic skin inflammation [RNA-Seq]. Homo sapiens

Environmental stimuli are known to contribute to psoriasis pathogenesis and that of other autoimmune diseases, but the mechanism is unknown. Here we show that the aryl hydrocarbon receptor (AhR), a transcription factor that senses environmental stimuli, modulates pathology in psoriasis. AhR-activating ligands reduced inflammation in the lesional skin of psoriasis patients, whereas AhR antagonists upregulated inflammation. Similarly, AhR signaling via the endogenous FICZ ligand reduced the inflammatory response in the imiquimod-induced model of psoriasis and AhR deficient mice exhibited a substantial exacerbation of the disease, compared to AhR sufficient controls. Non-haematopoietic cells, in particular keratinocytes, were responsible for this hyper-inflammatory response, which involved increased reactivity to IL-1beta and upregulation of AP-1 family members of transcription factors. Thus, our data suggest a critical role for AhR in the regulation of inflammatory responses and open the possibility for novel therapeutic strategies in chronic inflammatory disorders. Overall design: Total RNA obtained from skin explants taken from psoriatic patients or healthy donors cultured in the presence of AhR agonist or antagonist

已知环境刺激可参与银屑病及其他自身免疫性疾病的发病过程，但其具体分子机制尚未阐明。本研究证实，作为可感知环境刺激的转录因子，芳香烃受体（aryl hydrocarbon receptor, AhR）可调控银屑病的病理进程。AhR激活配体可减轻银屑病患者皮损皮肤的炎症反应，而AhR拮抗剂则会加剧炎症。类似地，通过内源性配体FICZ介导的AhR信号通路可减轻咪喹莫特诱导的银屑病模型小鼠的炎症反应；与AhR功能完整的对照小鼠相比，AhR缺陷型小鼠的病情出现显著加重。非造血细胞（尤其是角质形成细胞）是这种过度炎症反应的介导主体，该反应涉及对IL-1β反应性的增强以及转录因子AP-1家族成员的表达上调。综上，本研究数据表明AhR在炎症反应调控中发挥关键作用，同时为慢性炎症性疾病的新型治疗策略提供了潜在可能。实验整体设计：从银屑病患者或健康志愿者获取的皮肤外植体，在添加AhR激动剂或拮抗剂的培养体系中培养后，提取总RNA。