Open AccessConditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis
Author(s) -
Javier Lozano-Gerona,
Aida Oliván-Viguera,
Pablo DelgadoWicke,
Vikrant Singh,
Brandon M. Brown,
Elena Tapia-Casellas,
Esther Pueyo,
Marta Sofía Valero,
A.L. García-Otín,
Pilar Giraldo,
Edgar Abarca-Lachen,
Joaquín C. Surra,
Jesús Osada,
Kirk L. Hamilton,
S. P. Raychaudhuri,
Miguel Marigil,
Ángeles Juarranz,
Heike Wulff,
Hiroto Miura,
Yolanda Gilaberte,
Ralf Köhler
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0222619
Subject(s) - spongiosis , hyperkeratosis , epidermis (zoology) , hyperplasia , acanthosis , transgene , biology , medicine , pathology , immunology , anatomy , biochemistry , gene
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 Ca 2+ -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.