KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype

Abstract

Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy. Netherton syndrome (NS) is a genetic skin disorder caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. In this work, we aimed to explore the molecular mechanisms underlying this disease using a novel mutant mouse model for NS, which is based on mimicking a causative mutation known from human patients. This novel model reproduces the symptoms of NS and thus provides a useful tool to study the NS pathology in a complex in vivo environment. Most importantly, by combination of this NS-mouse model with mutant mice individually or simultaneously deficient for proteases KLK5 and KLK7, we elucidated the complex proteolytic networks that are dysregulated in the absence of LEKTI. We show that although the single ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency, simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality. Our results also provide novel insights into the roles of KLK5 and KLK7 in the inflammation and differentiation defects that are associated with NS. Based on these findings, we propose that both, KLK5 and KLK7 should become targets for NS therapy.