Abstract
Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-β1 (60-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-β1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target.
Highlights
Ion channels have long been known to contribute to the pathophysiology of inflammatory, autoimmune [1], and proliferative diseases [2,3,4]
In the epidermis of the DOX-treated mice, we found foci of moderate intra-epidermal edema (Fig 3D), similar to spongiosis, which is characteristic of eczematous dermatitis [43]
Our results demonstrate that KCa3.1 over-expression was capable of causing a severe disturbance of epidermal homeostasis
Summary
Ion channels have long been known to contribute to the pathophysiology of inflammatory, autoimmune [1], and proliferative diseases [2,3,4]. KCa3.1 induction has been implicated in several diseases states characterized by excessive cell proliferation and inflammation Induction of KCa3.1 was shown to regulate the phenotypic switch of fibroblasts and smooth muscle cells towards a dedifferentiated proliferative phenotype that promoted pathological organ remodeling in the lung, heart, and kidneys [25,26,27,28,29,30], as well as arterial neointima formation [18, 31,32]. High expression of KCa3.1 has been considered a marker of tumor progression for some cancers [3, 33,34]
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