Research ArticleSKIN

Humidity-regulated CLCA2 protects the epidermis from hyperosmotic stress

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Science Translational Medicine  09 May 2018:
Vol. 10, Issue 440, eaao4650
DOI: 10.1126/scitranslmed.aao4650

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Humidity—Harbinger of health?

Low environmental humidity can aggravate symptoms of atopic dermatitis (AD), an inflammatory skin disease. Seltmann et al. investigated the link between humidity and epidermal barrier function. Using a mouse model that exhibits AD-like symptoms, they found that high humidity reduced epidermal thickness and skin inflammation. Chloride channel accessory 2 protein was highly expressed in keratinocytes in response to hyperosmotic stress, and it increased cell-cell adhesions and protected cells from apoptosis. This osmoregulated protein was up-regulated in skin samples from patients with AD, which suggests a compensatory mechanism to maintain epidermal barrier function.


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.

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