Verena Moosbrugger-Martinz

Role of PPAR, LXR, and PXR in epidermal homeostasis and inflammation

Epidermal lipid synthesis and metabolism are regulated by nuclear hormone receptors (NHR) and in turn epidermal lipid metabolites can serve as ligands to NHR. NHR form a large superfamily of receptors modulating gene transcription through DNA binding. A subgroup of these receptors is ligand-activated and heterodimerizes with the retinoid X receptor including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR) and pregnane X receptor (PXR). Several isotypes of these receptors exist, all of which are expressed in skin. In keratinocytes, ligand activation of PPARs and LXRs stimulates differentiation, induces lipid accumulation, and accelerates epidermal barrier regeneration. In the cutaneous immune system, ligand activation of all three receptors, PPAR, LXR, and PXR, has inhibitory properties, partially mediated by downregulation of the NF-kappaB pathway. PXR also has antifibrotic effects in the skin correlating with TGF-beta inhibition. In summary, ligands of PPAR, LXR and PXR exert beneficial therapeutic effects in skin disease and represent promising targets for future therapeutic approaches in dermatology. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

Alterations in Epidermal Eicosanoid Metabolism Contribute to Inflammation and Impaired Late Differentiation in FLG-Mutated Atopic Dermatitis.

Loss-of-function mutations in the FLG gene cause ichthyosis vulgaris (IV) and represent the major predisposing genetic risk factor for atopic dermatitis (AD). Although both conditions are characterized by epidermal barrier impairment, AD also exhibits signs of inflammation. This work was aimed at delineating the role of FLG loss-of-function mutations on eicosanoid metabolism in IV and AD. Using human epidermal equivalents (HEEs) generated with keratinocytes isolated from nonlesional skin of patients with FLG wild-type AD (WT/WT), FLG-mutated AD (FLG/WT), IV (FLG/FLG), or FLG WT control skin, we assessed the potential autocrine role of epidermal-derived eicosanoids in FLG-associated versus FLG-WT AD pathogenesis. Ultrastructural analyses demonstrated abnormal stratum corneum lipid architecture in AD and IV HEEs, independent of FLG genotype. Both AD (FLG/WT) and IV (FLG/FLG) HEEs showed impaired late epidermal differentiation. Only AD (FLG/WT) HEEs exhibited significantly increased levels of inflammatory cytokines. Analyses of lipid mediators revealed increased arachidonic acid and 12-lipoxygenase metabolites. Whereas treatment of control HEEs with arachidonic acid increased expression of inflammatory cytokines, 12-hydroxy-eicosatetraenoic acid attenuated expression of late differentiation markers. Thus, FLG mutations lead to alterations in epidermal eicosanoid metabolism that could serve as an autocrine trigger of inflammation and impaired late epidermal differentiation in AD.

Enhanced expression of genes related to xenobiotic metabolism in the skin of patients with atopic dermatitis but not with ichthyosis vulgaris

Previous transcriptome analyses underscored the importance of immunological and skin barrier abnormalities in atopic dermatitis (AD). We sought to identify pathogenic pathways involved in AD by comparing the transcriptomes of AD patients stratified for filaggrin (FLG)-null mutations to those of both healthy donors and patients with ichthyosis vulgaris. We applied RNA sequencing to analyze the whole transcriptome of nonlesional skin. We found that 607 genes (476 up-regulated and 131 down-regulated by >2-fold) and 193 genes (172 up-regulated and 21 down-regulated by >2-fold) were differentially expressed when all AD or ichthyosis vulgaris patients were compared with healthy donors, respectively. Expression of genes involved in RNA/protein turnover and adenosine triphosphate synthesis, as well as genes involved in cell death, response to oxidative stress, DNA damage/repair, and autophagy, were significantly enriched in AD skin and, to a lesser extent, in ichthyosis vulgaris skin. FLG-null mutations appear to hardly interfere with current observations. Genes related to xenobiotic metabolism were up-regulated in AD skin only, as were genes related to arachidonic, linoleic, and α-linolenic acid metabolism. Thus, this work newly links AD pathogenesis to aberrant expression of genes related to xenobiotic metabolism.

A Mouse Model for Atopic Dermatitis Using Topical Application of Vitamin D3 or of Its Analog MC903.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with pruritus and high prevalence. Indeed, 15-30 % of children and 2-10 % of adults from industrialized countries are affected. Acute AD lesions are characterized by epidermal hyperplasia associated with a dominant Th2/Th17 immune response and dermal inflammatory infiltrates. Moreover, the expression of alarmins such as TSLP, IL-33, and IL-25 is upregulated in acute AD lesions. Topical application of vitamin D3 or of its low-calcemic analog MC903 induces changes in skin morphology and inflammation resembling immune perturbations observed in acute lesions of patients with AD. Mice treated with MC903 or vitamin D3 additionally display increased serum IgE levels, as observed in patients with extrinsic AD. Interestingly, these symptoms are not dependent on mouse gender or on genetic background. Thus, the easiness of this mouse model renders it very attractive to study immunologic abnormalities involved in AD development or maintenance. Furthermore, this model might be useful for preclinical studies aiming at unraveling new therapeutic strategies to treat AD. In this chapter, we describe the induction and major features of MC903 and vitamin D3-induced AD-like inflammation in mice.

2nd Science Days of the Austrian Society of Dermatology and Venereology (ÖGDV Forschungstage): Forum - ÖGDV

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Epidermale Barriere bei hereditären Ichthyosen, atopischer Dermatitis und Psoriasis

Zahlreiche Hautkrankheiten gehen mit Störungen der Hautbarriere einher. Man unterscheidet primäre und sekundäre Barrierestörungen. Erstere sind monogen durch Defekte in Schlüsselkomponenten der Epidermis bedingt (z.B. Ichthyosen). Sekundäre Barrierestörungen treten bei entzündlichen Hautkrankheiten auf, bei denen die epidermale Homöostase beeinträchtigt ist (z.B. Ekzeme, Psoriasis u.v.a.m.). Bei diesen Erkrankungen hemmt die Entzündung den Aufbau oder Erhalt intakter Barrierstrukturen. Neue Forschungsergebnisse sprechen dafür, dass bei der atopischen Dermatitis und in geringerem Maß bei der Psoriasis eine Kombination primärer und sekundärer Barrierestörungen vorliegt. Voraussichtlich lassen sich zukünftig Subtypen dieser Erkrankungen definieren, bei denen die eine oder die andere Komponente im Vordergrund steht.