Natural Products Research Institute, Korea Institute of Science and Technology (KIST), Gangneung 25451, Korea.
Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Korea.
Int J Mol Sci. 2022 Aug 4;23(15):8687. doi: 10.3390/ijms23158687.
The skin acts as a mechanical barrier that protects the body from the exterior environment, and skin barrier function is attributed to the stratum corneum (SC), which is composed of keratinocytes and skin lipids. Skin barrier homeostasis is maintained by a delicate balance between the differentiation and exfoliation of keratinocytes, and keratinocyte desquamation is regulated by members of the serine protease kalikrein (KLK) family and their endogenous inhibitor SPINK5/LEKTI (serine protease inhibitor Kazal type 5/lympho-epithelial Kazal-type-related inhibitor). Furthermore, SPINK5/LEKTI deficiency is involved in impaired skin barrier function caused by KLK over-activation. We sought to determine whether increased SPINK5/LEKTI expression ameliorates atopic dermatitis (AD) by strengthening skin barrier function using the ethanol extract of (LCE) and its active compound, diosmetin, by treating human keratinocytes with UVB and using a DNCB-induced murine model of atopic dermatitis. LCE or diosmetin dose-dependently increased the transcriptional activation of SPINK5 promoter and prevented DNCB-induced skin barrier damage by modulating events downstream of SPINK5, that is, KLK, PAR2 (protease activated receptor 2), and TSLP (thymic stromal lymphopoietin). LCE or diosmetin normalized immune response in DNCB treated SKH-1 hairless mice as determined by reductions in serum immunoglobulin E and interleukin-4 levels and numbers of lesion-infiltrating mast cells. Our results suggest that LCE and diosmetin are good candidates for the treatment of skin barrier-disrupting diseases such as Netherton syndrome or AD, and that they do so by regulating SPINK5/LEKTI.
皮肤作为一种机械屏障，保护身体免受外部环境的侵害，而皮肤屏障功能归因于角质形成细胞和皮肤脂质组成的角质层（SC）。角质形成细胞的分化和脱落之间的微妙平衡维持着皮肤屏障的稳态，角质形成细胞的脱屑受丝氨酸蛋白酶激肽（KLK）家族成员及其内源性抑制剂 SPINK5/LEKTI（丝氨酸蛋白酶抑制剂 Kazal 型 5/淋巴上皮 Kazal 型相关抑制剂）的调节。此外，SPINK5/LEKTI 缺乏参与 KLK 过度激活引起的皮肤屏障功能受损。我们试图通过用乙醇提取物（LCE）及其活性化合物大豆黄素处理人角质形成细胞，用 UVB 处理，并使用 DNCB 诱导的特应性皮炎小鼠模型，来确定增加 SPINK5/LEKTI 表达是否通过增强皮肤屏障功能来改善特应性皮炎。LCE 或大豆黄素剂量依赖性地增加 SPINK5 启动子的转录激活，并通过调节 SPINK5 下游的事件（即 KLK、PAR2（蛋白酶激活受体 2）和 TSLP（胸腺基质淋巴细胞生成素））来防止 DNCB 诱导的皮肤屏障损伤。LCE 或大豆黄素通过降低血清免疫球蛋白 E 和白细胞介素-4 水平以及病变浸润肥大细胞的数量，使 DNCB 处理的 SKH-1 无毛小鼠的免疫反应正常化。我们的结果表明，LCE 和大豆黄素是治疗皮肤屏障破坏疾病（如 Netherton 综合征或 AD）的良好候选药物，它们通过调节 SPINK5/LEKTI 来实现这一目标。
