Malassezia pachydermatis up-regulates AhR related CYP1A1 gene and epidermal barrier markers in human keratinocytes

Abstract

Cytochrome P450 CYP1A1 and CYP1B1 enzymes are regulated by the aryl hydrocarbon receptor (AhR), a transcription factor activated by a variety of ligands among which Malassezia metabolites. In this study, we analyzed the modulation of CYP1A1, CYP1B1, and AhR in human keratinocytes infected with different strains of Malassezia pachydermatis, as well as the upregulation of some genes involved in the epidermal homeostasis. We demonstrated that all the strains induced AhR activation and its nuclear translocation in HaCaT cells infected for 24 h, compared to untreated cells. The expression of CYP1A1 and CYP1B1, prototypical markers of the AhR signaling pathway, were upregulated with the level of CYP1A1 mRNA approximately 100-fold greater than that for CYP1B1. Filaggrin, involucrin, and TGaseI, proteins involved in epidermal differentiation, were all modulated by Malassezia pachydermatis strains, with the strongest induction observed for filaggrin. By contrast, quinone oxidoreductase 1 (NQO1), which is part of the antioxidant defense system involved in detoxification, was not modulated in our experimental model. In conclusions, our findings suggest that Malassezia pachydermatis infection of human keratinocytes induces activation of the AhR, and increases the expression of its responsive genes and markers of epidermal differentiation, paving the way for occurrence/exacerbation of pathological skin conditions.

Malassezia‐derived aryl hydrocarbon receptor ligands enhance the CCL20/Th17/soluble CD163 pathogenic axis in extra‐mammary Paget's disease

“…Malassezia yeast represent one of the most well‐known microbial genera of the normal skin flora. Several Malassezia metabolites, particularly indirubin and tryptanthrin, are reportedly ligands of the AhR, which stimulates NHKCs to increase the production of CYP1A1 as well as proinflammatory and Th2 cytokines . In addition, Malassezia species indirectly increase MMP activity .…”

Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis

“…Under physiological conditions, endogenous AHR ligands, such as tryptophan photoproducts [15,26,83] and microbial bioproducts [17,19,87], may upregulate the expression of EDC genes via AHR activation and maintain the healthy epidermal barrier. In line with this, the expression of FLG, LOR, and IVL is downregulated in keratinocytes with AHR knockdown or in the presence of AHR antagonists during the terminal differentiation of keratinocytes [79].…”

“…Consistent with this, long-lasting activation of AHR by dioxins induces the exaggerated terminal differentiation of keratinocytes and sebocytes, leading to the development of chloracne [27][28][29]. In particular, the exaggerated AHR activation converts sebocyte differentiation from sebaceous cell differentiation to keratinocytic differentiation, which results in the loss of sebocytes and keratinous The expression of EDC genes is not stable, but is actively modulated by external stimuli, including ultraviolet irradiation and photoproducts [14,15], dioxins, and other oxidative pollutants [4,16], bioproducts of commensal or symbiotic microorganisms such as Malassezia and Staphylococcus epidermidis [17][18][19], cosmetics [20], and various phytochemicals [21][22][23][24][25]. These chemical stimulants activate the xenobiotic chemical sensor aryl hydrocarbon receptor (AHR), upregulate the expression of barrier-related proteins, and accelerate the terminal differentiation of keratinocytes [4,14,16,18,26].…”

Malassezia Yeasts in Veterinary Dermatology: An Updated Overview

“…A recent study suggested that M. pachydermatis is able to activate the aryl hydrocarbon receptor (AhR), a nuclear receptor and transcriptional regulator with pleiotropic effects that include down-regulation of immune stimulation, modification of melanogenesis and epidermal cell function, and inhibition of antagonistic microbes (Buommino et al, 2018). Since indole production was not detected in a study of 80 M. pachydermatis strains from canine otitis externa, AhR activation by M. pachydermatis might be associated with the release of compounds other than indolic metabolites (Kiss et al, 1996).…”