Abstract
Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that attracted a great attention for its therapeutic potential against different pathologies including skin diseases. However, although the efficacy in preclinical models and the clinical benefits of CBD in humans have been extensively demonstrated, the molecular mechanism(s) and targets responsible for these effects are as yet unknown. Herein we characterized at the molecular level the effects of CBD on primary human keratinocytes using a combination of RNA sequencing (RNA-Seq) and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS). Functional analysis revealed that CBD regulated pathways involved in keratinocyte differentiation, skin development and epidermal cell differentiation among other processes. In addition, CBD induced the expression of several NRF2 target genes, with heme oxygenase 1 (HMOX1) being the gene and the protein most upregulated by CBD. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrated that the induction of HMOX1 mediated by CBD, involved nuclear export and proteasomal degradation of the transcriptional repressor BACH1. Notably, we showed that the effect of BACH1 on HMOX1 expression in keratinocytes is independent of NRF2. In vivo studies showed that topical CBD increased the levels of HMOX1 and of the proliferation and wound-repair associated keratins 16 and 17 in the skin of mice. Altogether, our study identifies BACH1 as a molecular target for CBD in keratinocytes and sets the basis for the use of topical CBD for the treatment of different skin diseases including atopic dermatitis and keratin disorders.
Highlights
The skin serves as a protective barrier against the environment and is constantly exposed to insults which can lead to the generation of reactive oxygen species (ROS)
We characterized at the molecular level the effects of CBD on primary human keratinocytes using a combination of RNA sequencing (RNA-Seq) and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS)
CBD induced the expression of several nuclear factor erythroid 2-like 2 (NRF2) target genes, with heme oxygenase 1 (HMOX1) being the gene and the protein most upregulated by CBD
Summary
The skin serves as a protective barrier against the environment and is constantly exposed to insults which can lead to the generation of reactive oxygen species (ROS). Among NRF2 target genes is the stress inducible enzyme HMOX1 This enzyme catalyses the rate-limiting reaction in heme catabolism and has important antioxidant and anti-inflammatory properties [8,9]. Cannabidiol (CBD) is the best studied non-psychotropic phytocannabinoid and shows pleiotropic activities including antioxidant and anti-inflammatory effects [17,18,19,20]. Based on these properties, CBD might have therapeutic utility in a number of conditions including skin disorders. We show that topical CBD application in mice increased the levels of HMOX1 in the epidermis (in agreement with our results in cells) and induced the expression of wound-repair and proliferation associated keratins 16 and 17
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