Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct

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Item Type:	Article
Title:	Filaggrin deficiency leads to impaired lipid profile and altered acidification pathways in a 3D skin construct
Creators Name:	Vávrová, K., Henkes, D., Strüver, K., Sochorová, M., Školová, B., Witting, M.Y., Friess, W., Schreml, S., Meier, R.J., Schäfer-Korting, M., Fluhr, J.W. and Küchler, S.
Abstract:	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 A(2) (sPLA(2)) IIA, which converts phospholipids to fatty acids, was significantly more activated in FLG− than in FLG+. Although NHE-1 and sPLA(2) 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 sPLA(2)/NHE-1 acidification pathways of the skin and the impact of FLG insufficiency on skin lipid composition and organization in reconstructed skin are described.
Keywords:	Acids, Atopic Dermatitis, Filaggrin Proteins, Gene Knockdown Techniques, Group II Phospholipases A2, Hydrogen-Ion Concentration, Intermediate Filament Proteins, Lipid Metabolism, Nonesterified Fatty Acids, Permeability, Pyrrolidonecarboxylic Acid, Skin, Sodium-Hydrogen Exchangers, Urocanic Acid
Source:	The Journal of Investigative Dermatology
ISSN:	0022-202X
Publisher:	Nature Publishing Group
Volume:	134
Number:	3
Page Range:	746-753
Date:	March 2014
Official Publication:	https://doi.org/10.1038/jid.2013.402
PubMed:	View item in PubMed

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