INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France; University of Paris, Paris, France.
INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France; University of Paris, Paris, France; Department of Genetics, Necker Hospital for Sick Children (AP-HP), Paris, France.
J Invest Dermatol. 2020 Jun;140(6):1184-1194. doi: 10.1016/j.jid.2019.10.026. Epub 2020 Mar 10.
Netherton syndrome is a rare autosomal recessive skin disease caused by loss-of-function mutations in SPINK5 encoding LEKTI protein that results in unopposed activity of epidermal kallikrein-related peptidases (KLKs), mainly KLK5, KLK7, and KLK14. Although the function of KLK5 and KLK7 has been previously studied, the role of KLK14 in skin homeostasis and its contribution to Netherton syndrome pathogenesis remains unknown. We generated a transgenic murine model overexpressing human KLK14 (TghKLK14) in stratum granulosum. TghKLK14 mice revealed 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. Desmoglein (Dsg) 2 staining was increased, whereas Dsg3 and Dsg4 were markedly reduced. In vitro studies showed that hKLK14 directly cleaves recombinant human DSG3 and recombinant human DSG4, 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 Netherton syndrome.
Netherton 综合征是一种罕见的常染色体隐性皮肤疾病，由编码 LEKTI 蛋白的 SPINK5 功能丧失突变引起，导致表皮激肽释放酶相关肽酶（KLKs），主要是 KLK5、KLK7 和 KLK14 的活性不受抑制。尽管 KLK5 和 KLK7 的功能以前已经研究过，但 KLK14 在皮肤稳态中的作用及其对 Netherton 综合征发病机制的贡献仍不清楚。我们生成了一种在颗粒层过度表达人 KLK14（TghKLK14）的转基因鼠模型。TghKLK14 小鼠显示在颗粒层和毛囊中蛋白水解活性增加。当 hKLK14 过表达时，它们的毛发不会生长并且显示出主要的缺陷，具有增生性毛囊。TghKLK14 小鼠显示出异常的表皮过度增殖和分化。超微结构分析显示毛发皮质中的细胞分离和 Huxley 层的厚度增加。桥粒芯糖蛋白 2（Dsg）2 的染色增加，而 Dsg3 和 Dsg4 则明显减少。体外研究表明，hKLK14 可直接切割重组人 DSG3 和重组人 DSG4，表明它们的降解有助于毛发异常。它们的皮肤表现出炎症特征，IL-36 家族成员及其涉及固有免疫的下游靶基因的表达增强。这项体内研究确定 KLK14 是 Netherton 综合征中所见的毛发异常和皮肤炎症的重要贡献者。
