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

Lozano-Gerona, J. ; Oliván-Viguera, A. ; Delgado-Wicke, P. ; Singh, V. ; Brown, B.M. ; Tapia-Casellas, E. (Universidad de Zaragoza) ; Pueyo, E. (Universidad de Zaragoza) ; Valero, M.S. (Universidad de Zaragoza) ; Garcia-Otín, Á.L. ; Giraldo, P. ; Abarca-Lachen, E. ; Surra, J.C. (Universidad de Zaragoza) ; Osada, J. (Universidad de Zaragoza) ; Hamilton, K.L. ; Raychaudhuri, S.P. ; Marigil, M. ; Juarranz, Á. ; Wulff, H. ; Miura, H. ; Gilaberte, Y. (Universidad de Zaragoza) ; Köhler, R.

Resumen: 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-ß1 (60-fold), IL-6 (33-fold), and TNFa (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-ß1 (-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.

Idioma: Inglés

DOI: 10.1371/journal.pone.0222619

Año: 2020

Publicado en: PloS one 15, 3 (2020), e0222619 [18 pp.]
ISSN: 1932-6203

Factor impacto JCR: 3.24 (2020)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 26 / 73 = 0.356 (2020) - Q2 - T2

Factor impacto SCIMAGO: 0.99 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B04-17R
Financiación: info:eu-repo/grantAgreement/ES/DGA-FEDER/T39-17R-BSICoS
Financiación: info:eu-repo/grantAgreement/EUR/FP7/PEOPLE-MC-CIG
Financiación: info:eu-repo/grantAgreement/EC/H2020/638284/EU/Is your heart aging well? A systems biology approach to characterize cardiac aging from the cell to the body surface/MODELAGE
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS-CB06-07-1036
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FIS-PI16-02112
Financiación: info:eu-repo/grantAgreement/ES/MINECO/DPI2016-75458-R

Tipo y forma: Article (Published version)

Área (Departamento): Área Fisiología (Dpto. Farmac.Fisiol.y Med.L.F.)
Área (Departamento): Área Producción Animal (Dpto. Produc.Animal Cienc.Ali.)
Área (Departamento): Servicios. División Biomédica (Serv.Gral. Apoyo Investigación)
Área (Departamento): Área Teoría Señal y Comunicac. (Dpto. Ingeniería Electrón.Com.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
Área (Departamento): Área Dermatología (Dpto. Medicina, Psiqu. y Derm.)