- PMID: 36725458
- DOI: 10.1016/j.jdermsci.2023.01.008
Background: Cannabidiol, a non-psychoactive phytocannabinoid, has antioxidant and anti-inflammatory activity in keratinocytes. However, the signaling pathway through which cannabidiol exerts its effect on keratinocytes or whether it can modulate keratinocyte differentiation has not been fully elucidated yet.
Objective: We investigated whether cannabidiol modulates epidermal differentiation and scavenges reactive oxygen species through the aryl hydrocarbon receptor (AhR) in keratinocytes and epidermal equivalents.
Methods: We investigated the cannabidiol-induced activation of AhR using AhR luciferase reporter assay, qRT-PCR, western blot, and immunofluorescence assays. We also analyzed whether keratinocyte differentiation and antioxidant activity are regulated by cannabidiol-induced AhR activation.
Results: In both keratinocytes and epidermal equivalents, cannabidiol increased both the mRNA and protein expression of filaggrin, involucrin, NRF2, and NQO1 and the mRNA expression of the AhR target genes, including CYP1A1 and aryl hydrocarbon receptor repressor. Additionally, cannabidiol showed antioxidant activity that was attenuated by AhR knockdown or co-administration with an AhR antagonist. Moreover, cannabidiol increased the ratio of OVOL1/OVOL2 mRNA expression, which is a downstream regulator of AhR that mediates epidermal differentiation. In addition to increased expression of barrier-related proteins, cannabidiol-treated epidermal equivalent showed a more prominent granular layer than the control epidermis. The increased granular layer by cannabidiol was suppressed by the AhR antagonist.
Conclusion: Cannabidiol can be a modulator of the AhR-OVOL1-filaggrin axis and AhR-NRF2-NQO1 signaling, thus indicating a potential use of cannabidiol in skin barrier enhancement and reducing oxidative stress.
Keywords: AhR, Antioxidant, CBD, Epidermal equivalents, NHEKs, Skin barrier
Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Declaration of Competing Interest The authors have no conflict of interest to declare.
Induction of a chloracne phenotype in an epidermal equivalent model by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on aryl hydrocarbon receptor activation and is not reproduced by aryl hydrocarbon receptor knock down.J Dermatol Sci. 2014 Jan;73(1):10-22. doi: 10.1016/j.jdermsci.2013.09.001. Epub 2013 Sep 11.PMID: 24161567 Free PMC article.
Diosmin restores the skin barrier by targeting the aryl hydrocarbon receptor in atopic dermatitis.Phytomedicine. 2021 Jan;81:153418. doi: 10.1016/j.phymed.2020.153418. Epub 2020 Nov 25.PMID: 33302042
Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor.J Dermatol. 2015 Feb;42(2):171-80. doi: 10.1111/1346-8138.12717. Epub 2014 Dec 6.PMID: 25482884 Free PMC article.
Antioxidative Phytochemicals Accelerate Epidermal Terminal Differentiation via the AHR-OVOL1 Pathway: Implications for Atopic Dermatitis.Acta Derm Venereol. 2018 Nov 5;98(10):918-923. doi: 10.2340/00015555-3003.PMID: 29972223 Review.
Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor.J Dermatol Sci. 2015 Nov;80(2):83-8. doi: 10.1016/j.jdermsci.2015.07.011. Epub 2015 Jul 26.PMID: 26276439 Review.
LinkOut – more resources
Full Text Sources