Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis.
Acetamides
/ pharmacology
Animals
Cytokines
/ metabolism
Doxycycline
/ pharmacology
Eczema
/ drug therapy
Epidermis
/ pathology
Female
Homeostasis
/ genetics
Hyperplasia
/ drug therapy
Intermediate-Conductance Calcium-Activated Potassium Channels
/ antagonists & inhibitors
Keratinocytes
/ metabolism
Keratosis
/ drug therapy
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Skin
/ metabolism
Trans-Activators
/ metabolism
Transgenes
Trityl Compounds
/ pharmacology
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
28
08
2019
accepted:
13
02
2020
entrez:
10
3
2020
pubmed:
10
3
2020
medline:
28
5
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32150577
doi: 10.1371/journal.pone.0222619
pii: PONE-D-19-24253
pmc: PMC7062274
doi:
Substances chimiques
Acetamides
0
Cytokines
0
Intermediate-Conductance Calcium-Activated Potassium Channels
0
Kcnn4 protein, mouse
0
Trans-Activators
0
Trityl Compounds
0
Doxycycline
N12000U13O
senicapoc
TS6G201A6Q
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0222619Subventions
Organisme : NCATS NIH HHS
ID : TL1 TR001861
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001860
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL080173
Pays : United States
Organisme : NCRR NIH HHS
ID : P20 RR018751
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM099608
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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