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CYP1A1 enzymatic activity influences skin inflammation via regulation of the AHR pathway.

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journal contribution
posted on 26.05.2021, 09:24 by Mariela Kyoreva, Ying Li, Mariyah Hoosenally, Jonathan Hardman-Smart, Kirsten Morrison, Isabella Tosi, Mauro Tolaini, Guillermo Barinaga, Brigitta Stockinger, Ulrich Mrowietz, Frank O Nestle, Catherine Smith, Jonathan N Barker, Paola Di Meglio
The Aryl hydrocarbon Receptor (AHR) is an environmental sensor and transcription factor activated by a variety of man-made and natural ligands, which has recently emerged as critical regulator of homeostasis at barrier organs such as the skin. Activation of the AHR pathway down-modulates skin inflammatory responses in animal models and psoriasis clinical samples. Here, we identify CYP1A1 enzymatic activity as a critical regulator of beneficial AHR signalling 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 animals. Inhibition of CYP1A1 enzymatic activity ameliorated the skin immunopathology by restoring beneficial AHR signalling. Importantly, psoriasis patients displayed reduced activation of the AHR pathway and increased CYP1A1 enzymatic activity compared to 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 novel strategy to harness the anti-inflammatory effect exerted by activation of the AHR pathway in skin.

Funding

Crick (Grant ID: 10159, Grant title: Stockinger FC001159)

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