Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome

Thomas Bugge and colleagues report that the matriptase protease initiates an epidermal kallikrein proteolytic cascade in mice lacking Spink5, which encodes the serine protease inhibitor LEKTI. Loss of matriptase rescued some features of excessive proteolytic degradation of corneodesmosomes and inflammatory activation in LEKTI-deficient mice, which are a model of human Netherton syndrome. 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.