Malassezia Yeasts Produce a Collection of Exceptionally Potent Activators of the Ah (Dioxin) Receptor Detected in Diseased Human Skin

Abstract

Malassezia yeasts are commensal microorganisms which under insufficiently understood conditions can become pathogenic. We have previously shown that specific strains isolated from diseased human skin can preferentially produce agonists of the aryl hydrocarbon receptor (AhR), whose activation has been linked to certain skin diseases. Investigation of skin scale extracts from patients with Malassezia associated diseases demonstrated 10–1000 fold higher AhR activating capacity than control skin extracts. LC/MS/MS analysis of the patients’ extracts revealed the presence of indirubin, 6-formylindolo[3,2-b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin, and pityriacitrin. The same compounds were also identified in 9/12 Malassezia species culture extracts tested, connecting their presence in skin scales with this yeast. Studying the activity of the Malassezia culture-extracts and pure metabolites in HaCaT cells by Reverse Transcriptase Real-Time PCR revealed significant alterations in mRNA levels of the endogenous AhR-responsive genes Cyp1A1, Cyp1B1 and AhRR. Indirubin and FICZ activated AhR in HaCaT and human HepG2 cells with significantly higher, yet transient, potency as compared to the prototypical AhR ligand, dioxin. In loco synthesis of these highly potent AhR inducers by Malassezia yeasts could have a significant impact on skin homeostatic mechanisms and disease development.

<b><i>Staphylococcus epidermidis</i></b> Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

“…It has been shown that Malassezia yeasts are able to secrete various indole derivatives as putative AhR ligands that induced the AhR-responsive genes CYP1A1 and CYP1B1 in HaCaT keratinocytes [27]. Nonetheless, it has not been reported whether the AhR plays a role in human keratinocytes in the interaction between keratinocytes and bacteria.…”

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…In addition, hydrogen peroxide in skin of vitiligo patients can lead to formation of FICZ (Schallreuter et al, 2012). Common skin-resident yeasts, Malassezia spp., produce the AhR ligands FICZ, ICZ, pityriacitrin, and malassezin (Wille et al, 2001;Gaitanis et al, 2008;Magiatis et al, 2013). LCs produce AhR-dependently the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Jux et al, 2009;Nguyen et al, 2010), which converts tryptophan to kynurenines.…”

“…UV light induces CYP1A1 in human skin (Katiyar et al, 2000) and cultured human keratinocytes (Wei et al, 1999;Fritsche et al, 2007). Furthermore, the proposed endogenous AhR ligand FICZ has been detected in UVB-irradiated immortal human keratinocytes , in skin samples from vitiligo patients (Schallreuter et al, 2012), and in skin from patients with seborrheic dermatitis carrying commensal yeasts belonging to the genus Malassezia, which converts tryptophan to several AhR-activating compounds (Magiatis et al, 2013).…”

“…In fact, the catalytic efficiency of CYP1A1 for FICZ is close to the limit of diffusion (Wincent et al, 2009). FICZ has been identified in human skin (Wincent et al, 2009;Schallreuter et al, 2012;Magiatis et al, 2013), and FICZ-derived sulfate conjugates have been detected in human urine (Wincent et al, 2009). The current data suggest that FICZ can be formed via different pathways that lead to formation of indole-3-acetaldehyde, the precursor of FICZ, such as enzymatic deamination of tryptamine and oxidation of tryptophan by intracellular oxidants (Rannug et al, unpublished data).…”

Fungi on the Skin: Dermatophytes and Malassezia

“…Tryptophan metabolism produces a variety of indoles that are potent agonists of the aryl alcohol receptor. These indoles (malassezin, indolo[3,2-b] carbazole, pityriacitrin, and indirubin) were found in extracts of skin from SD and PV patients but not in healthy controls (Magiatis et al 2013). The first three of these materials were produced by M. furfur strains isolated from SD patients when these strains were cultivated in L-tryptophan agar (Gaitanis et al 2008).…”