Transgenic kallikrein 14 mice display major hair shaft defects associated with desmoglein 3 and 4 degradation, abnormal epidermal differentiation and Il-36 signature

Abstract Netherthon syndrome (NS) is a rare autosomal recessive skin disease caused by loss-of-function mutations in SPINK5 encoding Lymphoepithelial Kazal-Type-related Inhibitor (LEKTI) that results in unopposed activity of epidermal kallikrein-related peptidases (KLKs), mainly KLK5, KLK7 and KLK14. While the function of KLK5 and KLK7 has been previously studied, the role of KLK14 in skin homeostasis and its contribution to NS pathogenesis remain unknown. We generated a transgenic murine model overexpressing human KLK14 (TghKLK14) in stratum granulosum. TghKLK14 mice showed increased proteolytic activity in the granular layers and in hair follicles. Their hair did not grow and displayed major defects with hyperplastic hair follicles when hKLK14 was overexpressed. TghKLK14 mice displayed abnormal epidermal hyperproliferation and differentiation. Ultrastructural analysis revealed cell separation in the hair cortex and increased thickness of Huxley’s layer. Dsg2 staining was increased while Dsg3 and Dsg4 were markedly reduced. In vitro studies showed that hKLK14 directly cleaves rhDSG3 and rhDSG4, suggesting that their degradation contributes to hair abnormalities. Their skin showed an inflammatory signature, with enhanced expression of Il-36 family members and their downstream targets involved in innate immunity. This in vivo study identifies KLK14 as an important contributor to hair abnormalities and skin inflammation seen in NS.