In Vitro Models of Filaggrin-Associated Diseases
Reconstructed skin models are new and useful research tools to investigate fundamental processes of the skin homeostasis and the pathophysiology of skin diseases. Although still in its infancy, more research efforts need to be made in the field of filaggr
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In Vitro Models of FilaggrinAssociated Diseases Sarah Küchler
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Contents 8.1 Introduction ...................................................
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8.2 Filaggrin-Deficient Reconstructed Skin Models ....................................................
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8.3 Reconstructed Skin Models to Study the Function of Filaggrin ..............................
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Conclusion ..............................................................
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References ...............................................................
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S. Küchler, PhD Department of Pharmaceutical Sciences, Pharmacology/Toxicology, Freie Universität Berlin, Königin-Luise-Str. 2-4, Berlin 14195, Germany e-mail: [email protected]
Introduction
Filaggrin gene (FLG) loss-of-function mutations contribute to several dermatological disorders such as ichthyosis vulgaris (IV) and atopic dermatitis (AD) [1, 2]. IV is the most prevalent cornification disorder and is often associated with AD [3, 4]. In both, IV and AD mutations in the FLG were discovered that are localized in the epidermal differentiation complex on chromosome 1q21 [1, 3]. Mutations in the FLG are the most widely occurring genetic risk factors for the development of AD known to date and have been identified in up to 20–40 % of the patients [5, 6]. Such mutations provoke an intercellular barrier abnormality that reduces the skin’s inflammatory threshold to topical irritants and antigens, triggering inflammatory processes [7–9]. The most common mutations occurring in approximately 9 % of the European population are R501X and 2282del4 [1, 10]. Various other common and rare mutations are also known but with lower prevalence [11, 12], suggesting that the real mutation frequency is even higher. Although FLG mutations are the most common mutations in prominent skin disorders such as IV and AD, the overall impact of the filaggrin deficiency on the pathogenesis is not yet completely understood yet. To gain more insight and to understand the fundamental processes resulting from the mutations, filaggrin-deficient skin models can be useful research tools. In most animal studies, the flaky tail (ft) mouse serves as a model system for filaggrin-deficient skin diseases because
J.P. Thyssen, H. Maibach (eds.), Filaggrin, DOI 10.1007/978-3-642-54379-1_8, © Springer-Verlag Berlin Heidelberg 2014
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S. Küchler
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these mice exhibit a barrier dysfunction similar to AD patients [13]. ft mice are characterized by a dry and flaky skin, an impaired barrier function, and higher susceptibility to skin irritation caused by a pro-filaggrin, which cannot be further processed to filaggrin monomers and fails to form keratohyalin granules [7, 8, 14]. Considering the findings of Harding and Scott in 1983, filaggrin data obtained from animal studies should be interpreted cautiously due to high species-related variability in the behavior of filaggrin [15]. Additionally, more evidence emerges that animal models do not provide reliable and predictive data for humans, especially when the immune system is involved, as it
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