Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis

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...

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Veröffentlicht in:PloS one 2020-03, Vol.15 (3), p.e0222619-e0222619
Hauptverfasser: Lozano-Gerona, Javier, Oliván-Viguera, Aida, Delgado-Wicke, Pablo, Singh, Vikrant, Brown, Brandon M, Tapia-Casellas, Elena, Pueyo, Esther, Valero, Marta Sofía, Garcia-Otín, Ángel-Luis, Giraldo, Pilar, Abarca-Lachen, Edgar, Surra, Joaquín C, Osada, Jesús, Hamilton, Kirk L, Raychaudhuri, Siba P, Marigil, Miguel, Juarranz, Ángeles, Wulff, Heike, Miura, Hiroto, Gilaberte, Yolanda, Köhler, Ralf
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Sprache:eng
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Zusammenfassung: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0222619