CYP1A1 Enzymatic Activity Influences Skin Inflammation Via Regulation of the AHR Pathway

Abstract

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.

Particle Size and Biological Fate of ZnO Do Not Cause Acute Toxicity, but Affect Toxicokinetics and Gene Expression Profiles in the Rat Livers after Oral Administration

“…These findings suggest that repeated administration of N-ZnO is more likely to affect immune response than B-ZnO. It was reported that CYP1A1 was highly expressed in inflammatory macrophages and the mice skin, inducing release of pro-inflammatory mediators and immune cell activation [50,51]. Hence, signaling pathway involving inflammation response can be a target for further mechanistic toxicity study.…”

Lung epithelial CYP1 activity regulates aryl hydrocarbon receptor dependent allergic airway inflammation

“…Thus, enhanced CYP1A1 activity in the absence of CYP1B1 may explain a comparable defect of immune regulation in AhR -/- and CYP1B1 -/- animals upon repetitive contact with aeroallergens. Indeed, the activity of individual CYP1 members are able to differentially modulate the availability of local AhR ligands thereby regulating AhR activity in hematopoietic cells such as ILC2s or macrophages, known players in AAI expressing AhR 15 , in analogy to a similar scenario recently proposed for intestinal ECs and skin keratinocytes 5, 40 .…”

The aryl hydrocarbon receptor at the forefront of host‐microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications

“…Indeed, individual clinical isolates may differ, and reflect interpersonal differences regarding the production of metabolites capable of AHR activation. 53 To date, only few studies exist addressing AHR signalling in skin investigated patient cohorts 33,34,48 from a microbiome perspective.…”

“…This concept was recently underscored by the finding that high levels of CYP1A1 enzymatic activity lead to exaggerated skin inflammation and phenocopy AHR deficient mice. 48 The authors proposed that CYP1A1 may deplete the AHR natural ligand pool in the skin (eg microbial metabolites or the UV‐irradiation generated molecule FICZ)) by phase I metabolism and thereby release the break that AHR normally holds on skin inflammation. Unfortunately, metabolomic analysis to determine actual metabolite levels, composition and source were lacking and remain to be further explored.…”

“…To date, only few studies exist addressing AHR signalling in skin investigated patient cohorts 33 , 34 , 48 from a microbiome perspective. Because these had only small sample numbers (<20 per group), there is a need for integrated multi‐omics approaches to investigate and correlate microbiome composition (16S rRNA gene sequencing or ideally metagenomics) with microbial metabolome and host transcriptome/epigenome.…”