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.

Transcriptomic and lipidomic profiling of eicosanoid/docosanoid signalling in affected and non‐affected skin of human atopic dermatitis patients

“…Atopic dermatitis is a chronic inflammatory skin disease with a prominent involvement of eicosanoids/docosanoids . In this study, we made a comprehensive screening of these eicosanoids and docosanoids as well as expression of eicosanoid/docosanoid metabolizing enzymes, binding proteins and receptors in affected and non‐affected skin of AD patients compared to skin of healthy volunteers.…”

3D skin models for 3R research: The potential of 3D reconstructed skin models to study skin barrier function

“…Experimental models have used foreskin keratinocytes, adult primary keratinocytes or an immortalized keratinocyte cell line to generate HSEs. Knock‐down strategies varied from transient knock‐down using siRNA to stable transduction using lentiviral delivery of FLG‐targeting shRNA . Most of these studies obtained a significant reduction in FLG mRNA or protein expression (70%‐90%), but none of them reached complete absence of expression.…”

“…Most of these studies obtained a significant reduction in FLG mRNA or protein expression (70%‐90%), but none of them reached complete absence of expression. More recently, we and others have used patient‐derived keratinocytes obtained from ichthyosis vulgaris (IV) patients carrying homozygous FLG loss‐of‐function mutations to generate HEEs and study in vitro skin barrier function . This provides a unique possibility to study the role of FLG in skin barrier defects, reported for both IV and AD.…”

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature

“…Data derived from animal or human models suggest abnormalities in cornification, lipid homeostasis, and keratinocyte adhesion/desquamation among various ichthyoses, implying shared defects in barrier architecture. [18][19][20][21][22][23][24][25][26] Human skin and blood studies have been limited to a few patients or select ichthyosis subtypes and have shown abnormalities in lipid, cornified envelope (CE), and/or other differentiation measures. 18,[27][28][29][30][31][32][33][34][35][36][37][38][39][40] Several observations link ichthyoses, particularly Netherton syndrome (NS), to atopic dermatitis (AD), which is marked by epidermal barrier defects and immune dysregulation.…”