AhRimmunity Lab, The Francis Crick Institute, London, United Kingdom.
St John's Institute of Dermatology, King's College London, London, United Kingdom.
J Invest Dermatol. 2021 Jun;141(6):1553-1563.e3. doi: 10.1016/j.jid.2020.11.024. Epub 2020 Dec 29.
The AHR is an environmental sensor and transcription factor activated by a variety of man-made and natural ligands, which has recently emerged as a critical regulator of homeostasis at barrier organs such as the skin. Activation of the AHR pathway downmodulates skin inflammatory responses in animal models and psoriasis clinical samples. In this study, we identify CYP1A1 enzymatic activity as a critical regulator of beneficial AHR signaling in the context of skin inflammation. Mice constitutively expressing Cyp1a1 displayed increased CYP1A1 enzymatic activity in the skin, which resulted in exacerbated immune cell activation and skin pathology, mirroring that observed in Ahr-deficient mice. Inhibition of CYP1A1 enzymatic activity ameliorated the skin immunopathology by restoring beneficial AHR signaling. Importantly, patients with psoriasis displayed reduced activation of the AHR pathway and increased CYP1A1 enzymatic activity compared with healthy donors, suggesting that dysregulation of the AHR/CYP1A1 axis may play a role in inflammatory skin disease. Thus, modulation of CYP1A1 activity may represent a promising alternative strategy to harness the anti-inflammatory effect exerted by activation of the AHR pathway in the skin.
AHR 是一种环境传感器和转录因子，可被多种人为和天然配体激活，它最近已成为皮肤等屏障器官内稳态的关键调节因子。AHR 通路的激活可下调动物模型和银屑病临床样本中的皮肤炎症反应。在这项研究中，我们确定 CYP1A1 酶活性是皮肤炎症背景下有益的 AHR 信号的关键调节因子。在皮肤中持续表达 Cyp1a1 的小鼠表现出 CYP1A1 酶活性增加，导致免疫细胞激活和皮肤病理学加剧，与 Ahr 缺陷型小鼠观察到的情况类似。抑制 CYP1A1 酶活性可通过恢复有益的 AHR 信号来改善皮肤免疫病理学。重要的是，与健康供体相比，银屑病患者的 AHR 通路激活减少，CYP1A1 酶活性增加，表明 AHR/CYP1A1 轴的失调可能在炎症性皮肤病中起作用。因此，调节 CYP1A1 活性可能代表一种有前途的替代策略，可利用 AHR 通路在皮肤中的抗炎作用。
