Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation

Valérie Pendaries, Jeremy Malaisse, Laurence Pellerin, Marina Le Lamer, Rachida Nachat, Sanja Kezic, Anne Marie Schmitt, Carle Paul, Yves Poumay, Guy Serre, Michel Simon

Research output: Contribution to journalArticle

Abstract

Atopic dermatitis is a chronic inflammatory skin disorder characterized by defects in the epidermal barrier and keratinocyte differentiation. The expression of filaggrin, a protein thought to have a major role in the function of the epidermis, is downregulated. However, the impact of this deficiency on keratinocytes is not really known. This was investigated using lentivirus-mediated small-hairpin RNA interference in a three-dimensional reconstructed human epidermis (RHE) model, in the absence of other cell types than keratinocytes. Similar to what is known for atopic skin, the experimental filaggrin downregulation resulted in hypogranulosis, a disturbed corneocyte intracellular matrix, reduced amounts of natural moisturizing factor components, increased permeability and UV-B sensitivity of the RHE, and impaired keratinocyte differentiation at the messenger RNA and protein levels. In particular, the amounts of two filaggrin-related proteins and one protease involved in the degradation of filaggrin, bleomycin hydrolase, were lower. In addition, caspase-14 activation was reduced. These results demonstrate the importance of filaggrin for the stratum corneum properties/functions. They indicate that filaggrin downregulation in the epidermis of atopic patients, either acquired or innate, may be directly responsible for some of the disease-related alterations in the epidermal differentiation program and epidermal barrier function.

Original languageEnglish
Pages (from-to)2938-2946
Number of pages9
JournalThe journal of investigative dermatology
Volume134
Issue number12
DOIs
Publication statusPublished - 2014

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Pendaries, V., Malaisse, J., Pellerin, L., Le Lamer, M., Nachat, R., Kezic, S., Schmitt, A. M., Paul, C., Poumay, Y., Serre, G., & Simon, M. (2014). Knockdown of filaggrin in a three-dimensional reconstructed human epidermis impairs keratinocyte differentiation. The journal of investigative dermatology, 134(12), 2938-2946. https://doi.org/10.1038/jid.2014.259