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.

低环境湿度会加重炎症性皮肤病特应性皮炎（AD）的症状。使用显示AD样体征的小鼠，我们表明环境湿度的增加可以挽救其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的表皮溶解产物进行的蛋白质组学定量分析确定了湿度调节的蛋白质，包括氯化物通道附件3A2（CLCA3A2），这是一种在皮肤中功能未知的蛋白质。AD患者的表皮，干燥条件下的器官型皮肤培养以及暴露于高渗压力下的培养的角质形成细胞显示出非直系同源人类CLCA2的上调。高渗性诱导的CLCA2通过p38 / c-Jun N端激酶激活转录因子2信号传导进行表达。CLCA2敲低促进高渗应激诱导的角质形成细胞凋亡，这是通过损害细胞黏附来实现的。这些发现为高环境湿度对AD患者的有益作用提供了机械解释，并将CLCA3A2 / CLCA2上调确定为保护角质形成细胞免受低湿度诱导的损害的机制。