The Enigma of AHR Activation in the Skin: Interplay among Ligands, Metabolism, and Bioavailability
| Autor: | Ellen H. van den Bogaard, Gary H. Perdew |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
FICZ 6-formylindolo[3 2-b]carbazole Biological Availability Inflammation Dermatology Pharmacology Ligands Therapeutic targeting Biochemistry complex mixtures Article Dermatitis Atopic Th17 T helper type 17 03 medical and health sciences 0302 clinical medicine polycyclic compounds medicine otorhinolaryngologic diseases Humans heterocyclic compounds Molecular Biology Skin chemistry.chemical_classification EROD ethoxyresorufin-O-deethylase integumentary system KC keratinocyte K keratin Cell Biology Metabolism respiratory system Bioavailability respiratory tract diseases α-NF α-naphthoflavone 030104 developmental biology Enzyme Receptors Aryl Hydrocarbon Skin cell chemistry 030220 oncology & carcinogenesis Original Article PAH polycyclic aromatic hydrocarbon medicine.symptom Coal tar ointment Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] Homeostasis |
| Zdroj: | Journal of Investigative Dermatology, 141, 1385-1388 J Invest Dermatol Journal of Investigative Dermatology, 141, 6, pp. 1385-1388 The Journal of Investigative Dermatology |
| ISSN: | 0022-202X |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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