Deficiency in the serine protease inhibitor LEKTI is the etiological origin of 
Netherton syndrome, which causes detachment of the stratum corneum and chronic 
inflammation. Here we show that the membrane protease matriptase initiates 
Netherton syndrome in a LEKTI-deficient mouse model by premature activation of a 
pro-kallikrein cascade. Auto-activation of pro-inflammatory 
pro-kallikrein-related peptidases that are associated with stratum corneum 
detachment was either low or undetectable, but they were efficiently activated 
by matriptase. Ablation of matriptase from LEKTI-deficient mice dampened 
inflammation, eliminated aberrant protease activity, prevented detachment of the 
stratum corneum, and improved the barrier function of the epidermis. These 
results uncover a pathogenic matriptase-pro-kallikrein pathway that could 
operate in several human skin and inflammatory diseases.