title: Alterations in Epidermal Eicosanoid Metabolism Contribute to Inflammation and Impaired Late Differentiation in FLG-Mutated Atopic Dermatitis.
abstract: 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.
authors: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Stefan
authors: S
authors: Blunder
authors: MTA-DE Public Health Research Group of the Hungarian Academy of Sciences, Faculty of Public Health, University of Debrecen, Debrecen, Hungary; Paprika Bioanalytics, Debrecen, Hungary.
authors: Ralph
authors: R
authors: Rühl
authors: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Verena
authors: V
authors: Moosbrugger-Martinz
authors: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Christine
authors: C
authors: Krimmel
authors: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Anita
authors: A
authors: Geisler
authors: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria; Department of Dermatology, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China.
authors: Huiting
authors: H
authors: Zhu
authors: Department of Dermatology, University of California, San Francisco, California, USA.
authors: Debra
authors: D
authors: Crumrine
authors: Department of Dermatology, University of California, San Francisco, California, USA.
authors: Peter M
authors: PM
authors: Elias
authors: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria; Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Robert
authors: R
authors: Gruber
authors: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria.
authors: Matthias
authors: M
authors: Schmuth
authors: Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: sandrine.dubrac@i-med.ac.at.
authors: Sandrine
authors: S
authors: Dubrac
mesh_terms: D000328:Adult; D001706:Biopsy; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D000091344:Filaggrin Proteins; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016112:Ichthyosis Vulgaris / Q000235:genetics; D007249:Inflammation / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D015777:Eicosanoids; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins