Infection, Immunity, Inflammation, and Physiological Medicine Programme, Immunobiology Section, University College London Institute of Child Health, London, United Kingdom.
Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
J Allergy Clin Immunol. 2017 Nov;140(5):1310-1322.e5. doi: 10.1016/j.jaci.2017.01.025. Epub 2017 Feb 24.
Upregulation of kallikreins (KLKs) including KLK5 has been reported in atopic dermatitis (AD). KLK5 has biological functions that include degrading desmosomal proteins and inducing proinflammatory cytokine secretion through protease-activated receptor 2 (PAR2). However, due to the complex interactions between various cells in AD inflamed skin, it is difficult to dissect the precise and multiple roles of upregulated KLK5 in AD skin.
We investigated the effect of upregulated KLK5 on the expression of epidermal-related proteins and cytokines in keratinocytes and on skin architecture.
Lesional and nonlesional AD skin biopsies were collected for analysis of morphology and protein expression. The relationship between KLK5 and barrier-related molecules was investigated using an ex vivo dermatitis skin model with transient KLK5 expression and a cell model with persistent KLK5 expression. The influence of upregulated KLK5 on epidermal morphology was investigated using an in vivo skin graft model.
Upregulation of KLK5 and abnormal expression of desmoglein 1 (DSG1) and filaggrin, but not PAR2 were identified in AD skin. PAR2 was increased in response to transient upregulation of KLK5, whereas persistently upregulated KLK5 did not show this effect. Persistently upregulated KLK5 degraded DSG1 and stimulated secretion of IL-8, IL-10, and thymic stromal lymphopoietin independent of PAR2 activity. With control of higher KLK5 activity by the inhibitor sunflower trypsin inhibitor G, restoration of DSG1 expression and a reduction in AD-related cytokine IL-8, thymic stromal lymphopoietin, and IL-10 secretion were observed. Furthermore, persistently elevated KLK5 could induce AD-like skin architecture in an in vivo skin graft model.
Persistently upregulated KLK5 resulted in AD-like skin architecture and secretion of AD-related cytokines from keratinocytes in a PAR2 independent manner. Inhibition of KLK5-mediated effects may offer potential as a therapeutic approach in AD.
在特应性皮炎（AD）中，激肽释放酶（KLKs）包括 KLK5 的表达上调已有报道。KLK5 具有生物功能，包括降解桥粒蛋白和通过蛋白酶激活受体 2（PAR2）诱导促炎细胞因子的分泌。然而，由于 AD 炎症皮肤中各种细胞之间的复杂相互作用，KLK5 在 AD 皮肤中的上调的精确和多种作用难以剖析。
我们研究了上调的 KLK5 对角质形成细胞中表皮相关蛋白和细胞因子表达以及皮肤结构的影响。
收集病变和非病变 AD 皮肤活检标本进行形态和蛋白表达分析。通过瞬时表达 KLK5 的体外皮炎皮肤模型和持续表达 KLK5 的细胞模型研究 KLK5 与屏障相关分子的关系。通过体内皮肤移植模型研究上调的 KLK5 对表皮形态的影响。
AD 皮肤中发现 KLK5 上调和桥粒芯糖蛋白 1（DSG1）和丝聚蛋白异常表达，但 PAR2 无异常。KLK5 的瞬时上调会导致 PAR2 增加，而持续上调 KLK5 则没有这种作用。持续上调的 KLK5 降解 DSG1 并刺激 IL-8、IL-10 和胸腺基质淋巴细胞生成素的分泌，而不依赖于 PAR2 活性。通过抑制剂向日葵胰蛋白酶抑制剂 G 控制 KLK5 活性，观察到 DSG1 表达的恢复以及 AD 相关细胞因子 IL-8、胸腺基质淋巴细胞生成素和 IL-10 分泌的减少。此外，持续升高的 KLK5 可在体内皮肤移植模型中诱导 AD 样皮肤结构。
持续上调的 KLK5 导致 AD 样皮肤结构和角质形成细胞中 AD 相关细胞因子的分泌，这种作用不依赖于 PAR2。抑制 KLK5 介导的作用可能为 AD 提供一种潜在的治疗方法。
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