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

Javier Lozano-Gerona, Aida Oliván-Viguera, Pablo Delgado-Wicke, Vikrant Singh, Brandon M. Brown, Elena Tapia-Casellas, Esther Pueyo, Marta Sofía Valero, Ángel Luis Garcia-Otín, Pilar Giraldo, Edgar Abarca-Lachen, Joaquín C. Surra, Jesús Osada, Kirk L. Hamilton, Siba P. Raychaudhuri, Miguel Marigil, Ángeles Juarranz, Heike Wulff, Hiroto Miura, Yolanda GilaberteRalf Köhler

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere0222619
JournalPloS one
Volume15
Issue number3
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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