Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe 
skin inflammation and scaling, a specific hair shaft defect and constant 
allergic manifestations. NS is caused by loss-of-function mutations in SPINK5 
(serine protease inhibitor of kazal type 5) encoding LEKTI-1 (lympho-epithelial 
kazal type related inhibitor type 5) expressed in stratified epithelia. In vitro 
and in vivo studies in murine models and in NS patients have cast light on the 
pathogenesis of the disease and shown that LEKTI deficiency results in unopposed 
kallikrein-related peptidase 5 (KLK5) and KLK7 activities and to the 
overactivity of a new epidermal protease, elastase 2 (ELA2). Two main cascades 
initiated by KLK5 activity have emerged. One results in desmoglein 1 degradation 
and desmosome cleavage leading to stratum corneum detachment. KLK5 also 
activates KLK7 and ELA2, which contribute to a defective skin barrier. This 
facilitates allergen and microbe penetration and generates danger signals 
leading to caspase 1 activation and the production of active interleukin-1β. In 
parallel, KLK5 activates a specific cascade of allergy and inflammation by 
activating protease-activated receptor-2 (PAR-2) receptors. PAR-2 activation 
triggers the production of the major pro-Th2 cytokine TSLP (thymic stromal 
lymphopoietin) and several inflammatory cytokines, including tumour necrosis 
factor-α. Levels of thymus and activation-regulated chemokine (TARC) and 
macrophage-derived chemokine (MDC) also contribute to allergy in a 
PAR-2-independent manner. Patient investigations have confirmed these 
abnormalities and revealed a wide spectrum of disease expression, sometimes 
associated with residual LEKTI expression. These results have demonstrated that 
the tight regulation of epidermal protease activity is essential for skin 
homeostasis and identified new targets for therapeutic intervention. They also 
provide a link with atopic dermatitis through deregulated protease activity, as 
recently supported by functional studies of the E420K LEKTI variant.