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¹ Institut National de la Santé et de la Recherche Médicale, U563, Toulouse F-31300, France
² Université Toulouse III Paul-Sabatier, Toulouse F-31400, France
³ Departement de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire de Toulouse, Toulouse F31000, France
⁴ EA2406 Université Bordeaux 2 Victor Segalen, Bordeaux F-33076, France

CORRESPONDENCE Alain Hovnanian: alain.hovnanian{at}inserm.fr

Netherton syndrome (NS) is a severe genetic skin disease with constant atopic manifestations that is caused by mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the protease inhibitor lymphoepithelial Kazal-type–related inhibitor (LEKTI). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. This skin barrier defect favors allergen absorption and is generally regarded as the underlying cause for atopy in NS. We show for the first time that the pro-Th2 cytokine thymic stromal lymphopoietin (TSLP), the thymus and activation-regulated chemokine, and the macrophage-derived chemokine are overexpressed in LEKTI-deficient epidermis. This is part of an original biological cascade in which unregulated kallikrein (KLK) 5 directly activates proteinase-activated receptor 2 and induces nuclear factor B–mediated overexpression of TSLP, intercellular adhesion molecule 1, tumor necrosis factor , and IL8. This proinflammatory and proallergic pathway is independent of the primary epithelial failure and is activated under basal conditions in NS keratinocytes. This cell-autonomous process is already established in the epidermis of Spink5^–/– embryos, and the resulting proinflammatory microenvironment leads to eosinophilic and mast cell infiltration in a skin graft model in nude mice. Collectively, these data establish that uncontrolled KLK5 activity in NS epidermis can trigger atopic dermatitis (AD)–like lesions, independently of the environment and the adaptive immune system. They illustrate the crucial role of protease signaling in skin inflammation and point to new therapeutic targets for NS as well as candidate genes for AD and atopy.

Abbreviations used: AD, atopic dermatitis; GR, granular layer; HRP, horseradish peroxidase; ICAM1, intercellular adhesion molecule 1; KLK, kallikrein; LC, Langerhans cell; LEKTI, lymphoepithelial Kazal-type–related inhibitor; Mdc, macrophage-derived chemokine; NHK, normal human primary keratinocytes; NS, Netherton syndrome; PAR2, proteinase-activated receptor 2; SC, stratum corneum; SPINK5, serine protease inhibitor Kazal-type 5; Tarc, thymus and activation-regulated chemokine; TSLP, thymic stromal lymphopoietin.

© 2009 Briot et al.
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This article has been cited by other articles:

• Sotiropoulou, G., Pampalakis, G., Diamandis, E. P. (2009). Functional Roles of Human Kallikrein-related Peptidases. J. Biol. Chem. 284: 32989-32994 [Abstract] [Full Text]  
• Briot, A., Deraison, C., Lacroix, M., Bonnart, C., Robin, A., Besson, C., Dubus, P., Hovnanian, A. (2009). Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. JCB 185: i7-i7 [Full Text]  

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