Deletion of the Epidermal Protease KLK5 Aggravates the Symptoms of Congenital Ichthyosis CDSN-nEDD

Congenital ichthyoses, now grouped under the acronym EDD (Epidermal Differentiation Disorders), include nonsyndromic forms (nEDD) that may be caused by loss-of-function mutations in the <i>CDSN</i> gene encoding corneodesmosin (<i>CDSN</i>-nEDD, formerly Peeling skin syndrome type 1). It is characterized by skin peeling, inflammation, itching and food allergies, while no specific therapy is currently available. High levels of KLK5, the serine protease that initiates the desquamation cascade, are found in the epidermis of <i>CDSN</i>-nEDD patients. Thus, we hypothesized that KLK5 inhibition would alleviate the symptoms of <i>CDSN</i>-nEDD and could serve as a new pharmacological target. A human epidermal equivalent (HEE) model for <i>CDSN</i>-nEDD was developed using shRNA-mediated <i>CDSN</i> knockdown. This model was characterized and used to assess the role of KLK5 knockdown on <i>CDSN</i>-nEDD. Also, <i>Klk5^-/-</i> mice were crossed with <i>Cdsn^epi-/-</i> mice, the murine model of <i>CDSN</i>-nEDD, to examine in vivo the effect(s) of <i>Klk5</i> deletion in <i>CDSN</i>-nEDD. Both models recapitulated the <i>CDSN</i>-nEDD desquamating phenotype. Elimination of KLK5 aggravated the <i>CDSN</i>-nEDD phenotype. Epidermal proteolysis was surprisingly elevated, while severe ultrastructural (corneo)desmosomal alterations increased epidermal barrier permeability and <i>stratum corneum</i> detachment was manifested. Based on these results, we concluded that targeting epidermal proteolysis with <i>KLK5</i> ablation cannot compensate for the loss of corneodesmosin and rescue over-desquamation of the <i>CDSN</i>-nEDD. Possibly, in the absence of KLK5, other proteases take over which increases the severity of over-desquamation in <i>CDSN-nEDD</i>. The translational outcome is that over-desquamation may not always be rescued by eliminating epidermal proteolysis, but fine protease modulation is more likely required.