A proinflammatory role of KLK6 protease in Netherton syndrome.

BACKGROUND

Netherton syndrome (NS) is a rare but severe type of ichthyosis characterized by atopy, allergies, and potentially lethal skin overdesquamation associated with highly elevated proteolytic activities in LEKTI-deficient epidermis. NS symptoms are recapitulated in Spink5 mouse where the gene encoding Lekti has been invalidated. Spink5 mice die within 5h from birth due to their severe skin barrier defect leading to dehydration. Spink5 mice also serve as a model for atopic dermatitis. The KLK6 protease is expressed by epidermal keratinocytes and shown in vitro to cleave desmosomal components.

OBJECTIVE

To investigate in vivo whether KLK6 is implicated in epidermal overdesquamation and/or inflammation associated with NS.

METHODS

The role of KLK6 was evaluated by generating Spink5Klk6 double knockout mice. The phenotype was assessed by macroscopic observation, immunohistochemistry for differentiation markers, in situ zymography for proteolysis, and quantification of proinflammatory cytokines.

RESULTS

Elimination of Klk6 in Spink5 remarkably suppresses the expression of Tslp, a major itching-inducing factor and driver of allergic reactions. Tnfα and the Th17 promoting cytokine Il-23 were also suppressed. Spink5Klk6 mice display normalized keratinocyte differentiation, nevertheless, epidermal proteolytic activities and the associated overdesquamation were not ameliorated, and Spink5Klk6 still died from a severe epidermal barrier defect as the Spink5.

CONCLUSIONS

Ablation of Klk6 largely suppresses epidermal inflammation but cannot rescue overdesquamation leading to the lethal NS phenotype. Nonetheless, our findings demonstrate for the first time that KLK6 is implicated in skin inflammation and may represent a novel druggable target for NS and other inflammatory conditions e.g. atopic dermatitis.