KCa3.1-overexpression in skin causes pruritic eczema and epidermal hyperplasi
Ion channels have emerged as potential mediators of chronic 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. 800-fold channel overexpression in keratinocytes of doxycycline-treated KCa3.1+ mice produced strong KCa3.1-functions, epidermal spongiosis, progressive epidermal hyperplasia, hyperkeratosis, itch and ulcers, and high morbidity within two weeks. We found significant induction of pro-proliferative and pro-inflammatory cytokines, IL-β1 (60-fold over basal levels), IL-23 (34-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. In-vivo treatment with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis, hyperplasia, and induction of IL-β1 (-88%), IL-23 (-77%), and IL-6 (-90%). In conclusion, KCa3.1-induction over basal levels in keratinocytes resulted in expression of several pro-proliferative and pro-inflammatory cytokines, spongiosis, hyperplasia, and hyperkeratosis, itch, and morbidity. This skin condition is similar to eczematous and psoriasiform dermatitis and identifies KCa3.1 as a key player in epidermal homeostasis and spongiosis. Clinically safe KCa3.1-blockers may be of therapeutic utility to treat spongiosis and itchy eczematous dermatitis.