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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Public Library of Science (PLoS)
2020-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0222619&type=printable |
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| author | 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 Gilaberte Ralf Köhler |
| author_facet | 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 Gilaberte Ralf Köhler |
| author_sort | Javier Lozano-Gerona |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-007ac73a43e4438e83b0321c8c8bf679 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-007ac73a43e4438e83b0321c8c8bf6792025-01-26T05:31:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01153e022261910.1371/journal.pone.0222619Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis.Javier Lozano-GeronaAida Oliván-VigueraPablo Delgado-WickeVikrant SinghBrandon M BrownElena Tapia-CasellasEsther PueyoMarta Sofía ValeroÁngel-Luis Garcia-OtínPilar GiraldoEdgar Abarca-LachenJoaquín C SurraJesús OsadaKirk L HamiltonSiba P RaychaudhuriMiguel MarigilÁngeles JuarranzHeike WulffHiroto MiuraYolanda GilaberteRalf KöhlerIon 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0222619&type=printable |
| spellingShingle | 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 Gilaberte Ralf Köhler Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis. PLoS ONE |
| title | Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis. |
| title_full | Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis. |
| title_fullStr | Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis. |
| title_full_unstemmed | Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis. |
| title_short | Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis. |
| title_sort | conditional kca3 1 transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0222619&type=printable |
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