Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 134, Issue 12, Pages 2938-2946Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/jid.2014.259
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Funding
- French National Center for Scientific Research (CNRS), Toulouse University
- French National Institute of Health and Medical Research (INSERM)
- European COST program SKINBAD [action BM0903]
- French Society for Dermatology (Societe Francaise de Dermatologie)
- Fondation pour la Dermatite Atopique
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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.
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