Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
24061166
DOI
10.1038/jid.2013.402
PII: S0022-202X(15)36674-4
Knihovny.cz E-zdroje
- MeSH
- atopická dermatitida metabolismus patologie MeSH
- filagriny MeSH
- fosfolipasy A2, skupina II metabolismus MeSH
- genový knockdown MeSH
- koncentrace vodíkových iontů MeSH
- kůže cytologie metabolismus MeSH
- kyselina pyrrolidonkarboxylová metabolismus MeSH
- kyselina urokanová metabolismus MeSH
- kyseliny mastné neesterifikované metabolismus MeSH
- kyseliny metabolismus MeSH
- lidé MeSH
- metabolismus lipidů fyziologie MeSH
- Na(+)-H(+) antiport metabolismus MeSH
- permeabilita MeSH
- proteiny intermediálních filament nedostatek genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- filagriny MeSH
- FLG protein, human MeSH Prohlížeč
- fosfolipasy A2, skupina II MeSH
- growth factor-activatable Na-H exchanger NHE-1 MeSH Prohlížeč
- kyselina pyrrolidonkarboxylová MeSH
- kyselina urokanová MeSH
- kyseliny mastné neesterifikované MeSH
- kyseliny MeSH
- Na(+)-H(+) antiport MeSH
- proteiny intermediálních filament 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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