Humidity-regulated CLCA2 protects the epidermis from hyperosmotic stress
Humidity-regulated CLCA2 protects the epidermis from hyperosmotic stress
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DOI：
10.1126/scitranslmed.aao4650
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发表时间：
2018-05-09
影响因子：
17.1
通讯作者：
Werner, Sabine
中科院分区：
文献类型：
--
作者：
Seltmann, Kristin;Meyer, Michael;Werner, Sabine
低环境湿度加重炎症性皮肤病特应性皮炎（AD）的症状。使用小鼠开发AD样的迹象，我们表明，增加环境湿度拯救他们的皮肤炎症和相关的表皮异常。对保持在低湿度或高湿度下的小鼠表皮裂解物进行定量蛋白质组学分析，鉴定了湿度调节蛋白，包括氯离子通道附件3A2（CLCA3A2），这是一种在皮肤中具有先前未知功能的蛋白质。AD患者的表皮、干燥条件下的器官型皮肤培养物和暴露于高渗应激的培养的角质形成细胞显示出非正交人类同源物CLCA 2的上调。高渗透压诱导的CLCA2表达通过p38/c-Jun N末端激酶激活转录因子2信号传导发生。CLCA2基因敲低可通过损害细胞间粘附促进高渗应激诱导的角质形成细胞凋亡。这些发现为高环境湿度对AD患者的有益作用提供了机制解释，并将CLCA 3A2/CLCA 2上调确定为保护角质形成细胞免受低湿度诱导的损伤的机制。
Low environmental humidity aggravates symptoms of the inflammatory skin disease atopic dermatitis (AD). Using mice that develop AD-like signs, we show that an increase in environmental humidity rescues their cutaneous inflammation and associated epidermal abnormalities. Quantitative proteomics analysis of epidermal lysates of mice kept at low or high humidity identified humidity-regulated proteins, including chloride channel accessory 3A2 (CLCA3A2), a protein with previously unknown function in the skin. The epidermis of patients with AD, organotypic skin cultures under dry conditions, and cultured keratinocytes exposed to hyperosmotic stress showed up-regulation of the nonorthologous human homolog CLCA2. Hyperosmolarity-induced CLCA2 expression occurred via p38/c-Jun N-terminal kinase-activating transcription factor 2 signaling. CLCA2 knockdown promoted keratinocyte apoptosis induced by hyperosmotic stress through impairment of cell-cell adhesion. These findings provide a mechanistic explanation for the beneficial effect of high environmental humidity for AD patients and identify CLCA3A2/CLCA2 up-regulation as a mechanism to protect keratinocytes from damage induced by low humidity.