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.

中文翻译：

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转基因激肽释放酶14小鼠显示出与Desmoglein 3和4降解，异常的表皮分化和IL-36签名相关的主要毛发轴缺陷。

Netherton综合征是一种罕见的常染色体隐性遗传性皮肤病，由编码LEKTI蛋白的SPINK5的功能丧失突变引起，这种突变导致表皮激肽释放酶相关肽酶（KLK）（主要是KLK5，KLK7和KLK14）的活性不受抑制。尽管KLK5和KLK7的功能已在以前进行过研究，但KLK14在皮肤动态平衡中的作用及其对Netherton综合征发病机制的贡献仍然未知。我们生成了在颗粒层中过表达人类KLK14（TghKLK14）的转基因鼠模型。TghKLK14小鼠显示出颗粒层和毛囊中的蛋白水解活性增加。当hKLK14过表达时，他们的头发没有生长，并显示出增生性毛囊的主要缺陷。TghKLK14小鼠表现出异常的表皮过度增殖和分化。超微结构分析显示，毛发皮层中的细胞分离，Huxley层的厚度增加。Desmoglein（Dsg）2染色增加，而Dsg3和Dsg4明显减少。体外研究表明，hKLK14直接裂解重组人DSG3和重组人DSG4，表明它们的降解导致头发异常。他们的皮肤表现出炎症特征，IL-36家族成员及其参与天然免疫的下游靶点表达增强。这项体内研究表明，KLK14是导致Netherton综合征中出现的头发异常和皮肤炎症的重要因素。体外研究表明，hKLK14直接裂解重组人DSG3和重组人DSG4，表明它们的降解导致头发异常。他们的皮肤表现出炎症特征，IL-36家族成员及其参与天然免疫的下游靶点的表达增强。这项体内研究表明，KLK14是导致Netherton综合征中出现的头发异常和皮肤发炎的重要因素。体外研究表明，hKLK14直接裂解重组人DSG3和重组人DSG4，表明它们的降解导致头发异常。他们的皮肤表现出炎症特征，IL-36家族成员及其参与天然免疫的下游靶点的表达增强。这项体内研究表明，KLK14是导致Netherton综合征中出现的头发异常和皮肤发炎的重要因素。