PPAR and Epidermal Eicosanoid Metabolism and cutaneous Function

The skin is an organ with very active lipid metabolism. In the outermost epidermal layer, called the stratum corneum, enucleated keratinocytes synthesize and deposit a lipid matrix which forms an essential barrier against desiccation and external assaults, e.g. microbes and allergens. The importance of a healthy skin barrier is demonstrated both by genetic diseases that drastically compromise epidermal barrier function in newborns, resulting in severe dehydration and death, and by an array of skin disorders showing skin barrier impairment (e.g. atopic dermatitis, psoriasis, various ichthyoses). Eicosanoids such as leukotrienes, monohydroxy fatty acids, prostaglandins and prostacyclins control key metabolic and immune-related pathways involved in skin homeostasis and epidermal barrier function. Indeed, mutations in genes coding for enzymes involved in eicosanoid synthesis (e.g. lipoxygenases) result in life-threatening diseases. However, the role of eicosanoids in skin barrier function remains poorly understood, and very little is known about the molecular regulation of these lipids in the living epidermal layers. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate gene transcription. All PPAR isoforms (PPAR-alpha, -beta/delta and -gamma) contribute to skin homeostastic processes, especially epidermal differentiation, lipid and energy metabolism, stratum corneum formation, and cutaneous inflammation. Importantly, fatty acid signaling molecules of the eicosanoid/docosanoid chemical class have been identified as PPAR ligands. We hypothesize that PPARs, by coordinating multiple biochemical pathways in keratinocytes, may be key targets for therapeutics aimed at normalizing barrier-related skin disorders. Deciphering the role of PPARs in skin homeostasis and especially in epidermal function by using state-of-the-art techniques as proposed in this application will significantly advance our understanding of the role(s) of PPARs in the epidermal barrier in health and disease. Indeed, many common skin diseases (e.g. atopic dermatitis, psoriasis, and contact dermatitis) exhibit impaired barrier function. Importantly, PPARs can be easily activated by drugs and/or lipids, and therefore they have become priority targets for new therapeutics to treat diverse skin conditions. Further advances in the treatment of epidermal barrier impairment are urgently awaited by an increasing number of patients.

Skin is an organ with very active lipid metabolism. In the outermost epidermal layer, called the horny layer, enucleated keratinocytes, called corneocytes, are surrounded by a well-characterized lipid matrix, which forms an essential barrier against desiccation and external assaults, e.g. microbes and allergens. Atopic dermatitis (eczema) is a skin disorder resulting from by primary defects of the skin barrier. Despite strong evidence for their importance in skin homeostasis, the role of signalling lipids, such as eicosanoids including leukotrienes, monohydroxy fatty acids, prostaglandins and prostacyclins, in skin barrier function remains poorly investigated. Indeed, little is known about the molecular regulation of these lipids in the living epidermal layers. Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate gene transcription. All PPAR isoforms (PPAR-alpha, -beta/delta and -gamma) contribute to skin homeostasis, with PPAR-alpha controlling epidermal differentiation, lipid metabolism, horny layer formation, skin pH and cutaneous inflammation, whereas PPAR-beta/delta and PPAR-gamma preferentially modulate energy metabolism in keratinocytes. Importantly, eicosanoids/docosanoids have been identified as PPAR ligands. Funding via the FWF helped us to delineate the role of eicosanoid and docosanoid metabolism in skin and in a very frequent disease called eczema. Results showed that eicosanoids deregulate keratinocyte differentiation, which ultimately leads to epidermal barrier dysfunction, and control local inflammation. Moreover, the role of PPAR in epidermal barrier homeostasis has been extensively studied. In summary, this project advanced the current knowledge about the role of eicosanoid/docosanoid metabolism in epidermal barrier homeostasis and open new perspectives on therapy for patients with eczema by challenging current concepts about the link between lipids and skin barrier function.