Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24061166
DOI
10.1038/jid.2013.402
PII: S0022-202X(15)36674-4
Knihovny.cz E-resources
- MeSH
- Dermatitis, Atopic metabolism pathology MeSH
- Filaggrin Proteins MeSH
- Group II Phospholipases A2 metabolism MeSH
- Gene Knockdown Techniques MeSH
- Hydrogen-Ion Concentration MeSH
- Skin cytology metabolism MeSH
- Pyrrolidonecarboxylic Acid metabolism MeSH
- Urocanic Acid metabolism MeSH
- Fatty Acids, Nonesterified metabolism MeSH
- Acids metabolism MeSH
- Humans MeSH
- Lipid Metabolism physiology MeSH
- Sodium-Hydrogen Exchangers metabolism MeSH
- Permeability MeSH
- Intermediate Filament Proteins deficiency genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Filaggrin Proteins MeSH
- FLG protein, human MeSH Browser
- Group II Phospholipases A2 MeSH
- growth factor-activatable Na-H exchanger NHE-1 MeSH Browser
- Pyrrolidonecarboxylic Acid MeSH
- Urocanic Acid MeSH
- Fatty Acids, Nonesterified MeSH
- Acids MeSH
- Sodium-Hydrogen Exchangers MeSH
- Intermediate Filament Proteins MeSH
Mutations in the filaggrin (FLG) gene are strongly associated with common dermatological disorders such as atopic dermatitis. However, the exact underlying pathomechanism is still ambiguous. Here, we investigated the impact of FLG on skin lipid composition, organization, and skin acidification using a FLG knockdown (FLG-) skin construct. Initially, sodium/hydrogen antiporter (NHE-1) activity was sufficient to maintain the acidic pH (5.5) of the reconstructed skin. At day 7, the FLG degradation products urocanic (UCA) and pyrrolidone-5-carboxylic acid (PCA) were significantly decreased in FLG- constructs, but the skin surface pH was still physiological owing to an upregulation of NHE-1. At day 14, secretory phospholipase A2 (sPLA2) IIA, which converts phospholipids to fatty acids, was significantly more activated in FLG- than in FLG+. Although NHE-1 and sPLA2 were able to compensate the FLG deficiency, maintain the skin surface pH, and ensured ceramide processing (no differences detected), an accumulation of free fatty acids (2-fold increase) led to less ordered intercellular lipid lamellae and higher permeability of the FLG- constructs. The interplay of the UCA/PCA and the sPLA2/NHE-1 acidification pathways of the skin and the impact of FLG insufficiency on skin lipid composition and organization in reconstructed skin are described.
Department of Dermatology Charité University Clinic Berlin Germany
Department of Dermatology University Medical Center Regensburg Regensburg Germany
Department of Pharmacy Ludwig Maximilians University Munich Munich Germany
Faculty of Pharmacy Charles University Prague Hradec Kralove Czech Republic
Institute for Pharmacy Pharmacology and Toxicology Freie Universität Berlin Berlin Germany
Institute of Analytical Chemistry Chemo and Biosensors University of Regensburg Regensburg Germany
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