TY - JOUR
T1 - Hallmarks of Atopic Skin Mimicked In Vitro by Means of a Skin Disease Model Based on FLG Knock-down
AU - Küchler, Sarah
AU - Henkes, Dominika
AU - Eckl, Katja-Martina
AU - Ackermann, Katharina
AU - Plendl, Johanna
AU - Korting, Hans-Christian
AU - Hennies, Hans-Christian
AU - Schäfer-Korting, Monika
N1 - 2011 FRAME.
PY - 2011/10
Y1 - 2011/10
N2 - Loss-of-function mutations in the filaggrin gene (FLG) are a strong predisposing factor for atopic dermatitis, although their relevance to the disease pathomechanism needs further elucidation. The generation of an in vitro model of atopic skin would not only permit further evaluation of the underlying pathogenetic mechanisms and the testing of new treatment options, but would also allow toxicological studies to be performed in a simple, rapid and inexpensive manner. In this study, we have knocked down FLG expression in human keratinocytes and created three-dimensional skin models, which we used to investigate the impact of FLG on epidermal maturation and on skin absorption and its response to irritation. Histopathological evaluation of the skin models showed impaired epidermal differentiation in the FLG knock-down model. In addition, skin irritation induced by an application of sodium dodecyl sulphate resulted in significantly higher lactate dehydrogenase leakage, and interleukin (IL)-6 and IL-8 levels, than in the control model. To assess the effect of filaggrin deficiency on skin absorption of topically applied agents, we quantified the percutaneous absorption of lipophilic and hydrophilic model drugs, finding clinical relevance only for lipophilic drugs. This study clearly demonstrates that important clinical characteristics of atopic skin can be mimicked by using in vitro skin models. The FLG knock-down construct is the first step toward an in vitro model that allows clinical and toxicological studies of atopic-like skin.
AB - Loss-of-function mutations in the filaggrin gene (FLG) are a strong predisposing factor for atopic dermatitis, although their relevance to the disease pathomechanism needs further elucidation. The generation of an in vitro model of atopic skin would not only permit further evaluation of the underlying pathogenetic mechanisms and the testing of new treatment options, but would also allow toxicological studies to be performed in a simple, rapid and inexpensive manner. In this study, we have knocked down FLG expression in human keratinocytes and created three-dimensional skin models, which we used to investigate the impact of FLG on epidermal maturation and on skin absorption and its response to irritation. Histopathological evaluation of the skin models showed impaired epidermal differentiation in the FLG knock-down model. In addition, skin irritation induced by an application of sodium dodecyl sulphate resulted in significantly higher lactate dehydrogenase leakage, and interleukin (IL)-6 and IL-8 levels, than in the control model. To assess the effect of filaggrin deficiency on skin absorption of topically applied agents, we quantified the percutaneous absorption of lipophilic and hydrophilic model drugs, finding clinical relevance only for lipophilic drugs. This study clearly demonstrates that important clinical characteristics of atopic skin can be mimicked by using in vitro skin models. The FLG knock-down construct is the first step toward an in vitro model that allows clinical and toxicological studies of atopic-like skin.
KW - Animals
KW - Cells, Cultured
KW - Dermatitis, Atopic
KW - Fibroblasts
KW - Gene Silencing
KW - Humans
KW - Intermediate Filament Proteins
KW - Keratinocytes
KW - Models, Biological
KW - Mutation
KW - Tissue Culture Techniques
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
UR - http://www.atla.org.uk/
M3 - Article
C2 - 22103940
VL - 39
SP - 471
EP - 480
JO - ATLA abstracts
JF - ATLA abstracts
SN - 0261-1929
IS - 5
ER -