Hallmarks of Atopic Skin Mimicked In Vitro by Means of a Skin Disease Model Based on FLG Knock-down

Sarah Küchler, Dominika Henkes, Katja-Martina Eckl, Katharina Ackermann, Johanna Plendl, Hans-Christian Korting, Hans-Christian Hennies, Monika Schäfer-Korting

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

LanguageEnglish
Pages471-480
Number of pages10
JournalATLA Alternatives to Laboratory Animals
Volume39
Issue number5
Publication statusPublished - Oct 2011
Externally publishedYes

Fingerprint

Gene Knockdown Techniques
Skin Diseases
Skin
Genes
Skin Absorption
Toxicology
Atopic Dermatitis
filaggrin
In Vitro Techniques
Interleukin-8
Keratinocytes
L-Lactate Dehydrogenase
Sodium Dodecyl Sulfate
Causality
Pharmaceutical Preparations
Interleukin-6
Gene expression
Gene Expression
Mutation

Cite this

Küchler, S., Henkes, D., Eckl, K-M., Ackermann, K., Plendl, J., Korting, H-C., ... Schäfer-Korting, M. (2011). Hallmarks of Atopic Skin Mimicked In Vitro by Means of a Skin Disease Model Based on FLG Knock-down. ATLA Alternatives to Laboratory Animals, 39(5), 471-480.
Küchler, Sarah ; Henkes, Dominika ; Eckl, Katja-Martina ; Ackermann, Katharina ; Plendl, Johanna ; Korting, Hans-Christian ; Hennies, Hans-Christian ; Schäfer-Korting, Monika. / Hallmarks of Atopic Skin Mimicked In Vitro by Means of a Skin Disease Model Based on FLG Knock-down. In: ATLA Alternatives to Laboratory Animals. 2011 ; Vol. 39, No. 5. pp. 471-480.
@article{71745cab86a74a5487df90cb58c968bf,
title = "Hallmarks of Atopic Skin Mimicked In Vitro by Means of a Skin Disease Model Based on FLG Knock-down",
abstract = "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.",
keywords = "Animals, Cells, Cultured, Dermatitis, Atopic, Fibroblasts, Gene Silencing, Humans, Intermediate Filament Proteins, Keratinocytes, Models, Biological, Mutation, Tissue Culture Techniques, Journal Article, Research Support, Non-U.S. Gov't",
author = "Sarah K{\"u}chler and Dominika Henkes and Katja-Martina Eckl and Katharina Ackermann and Johanna Plendl and Hans-Christian Korting and Hans-Christian Hennies and Monika Sch{\"a}fer-Korting",
note = "2011 FRAME.",
year = "2011",
month = "10",
language = "English",
volume = "39",
pages = "471--480",
journal = "ATLA Alternatives to Laboratory Animals",
issn = "0261-1929",
publisher = "FRAME",
number = "5",

}

Küchler, S, Henkes, D, Eckl, K-M, Ackermann, K, Plendl, J, Korting, H-C, Hennies, H-C & Schäfer-Korting, M 2011, 'Hallmarks of Atopic Skin Mimicked In Vitro by Means of a Skin Disease Model Based on FLG Knock-down', ATLA Alternatives to Laboratory Animals, vol. 39, no. 5, pp. 471-480.

Hallmarks of Atopic Skin Mimicked In Vitro by Means of a Skin Disease Model Based on FLG Knock-down. / Küchler, Sarah; Henkes, Dominika; Eckl, Katja-Martina; Ackermann, Katharina; Plendl, Johanna; Korting, Hans-Christian; Hennies, Hans-Christian; Schäfer-Korting, Monika.

In: ATLA Alternatives to Laboratory Animals, Vol. 39, No. 5, 10.2011, p. 471-480.

Research output: Contribution to journalArticle

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

VL - 39

SP - 471

EP - 480

JO - ATLA Alternatives to Laboratory Animals

T2 - ATLA Alternatives to Laboratory Animals

JF - ATLA Alternatives to Laboratory Animals

SN - 0261-1929

IS - 5

ER -

Küchler S, Henkes D, Eckl K-M, Ackermann K, Plendl J, Korting H-C et al. Hallmarks of Atopic Skin Mimicked In Vitro by Means of a Skin Disease Model Based on FLG Knock-down. ATLA Alternatives to Laboratory Animals. 2011 Oct;39(5):471-480.