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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Transgenes*; Eczema/*genetics ; Epidermis/*pathology ; Intermediate-Conductance Calcium-Activated Potassium Channels/*genetics ; Intermediate-Conductance Calcium-Activated Potassium Channels/*metabolism ; Keratosis/*genetics ; Skin/*metabolism; Acetamides/pharmacology ; Animals ; Cytokines/metabolism ; Doxycycline/pharmacology ; Eczema/drug therapy ; Female ; Homeostasis/genetics ; Hyperplasia/drug therapy ; Hyperplasia/genetics ; Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors ; Keratinocytes/metabolism ; Keratosis/drug therapy ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Trans-Activators/metabolism ; Trityl Compounds/pharmacology

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.
Competing Interests: The authors have declared that no competing interests exist.

Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1084-9. (PMID: 18309114)
PLoS One. 2015 Apr 07;10(4):e0122992. (PMID: 25848765)
Mol Pharmacol. 2015 Feb;87(2):338-48. (PMID: 25468883)
Adv Pharmacol. 2016;77:65-104. (PMID: 27451095)
Am J Physiol. 1996 Nov;271(5 Pt 1):L775-84. (PMID: 8944721)
Science. 2018 May 4;360(6388):508-513. (PMID: 29724949)
Circulation. 2003 Sep 2;108(9):1119-25. (PMID: 12939222)
Respir Res. 2014 Dec 05;15:155. (PMID: 25476248)
Int J Mol Sci. 2019 Mar 08;20(5):. (PMID: 30857243)
Int J Alzheimers Dis. 2012;2012:868972. (PMID: 22675649)
Clin Sci (Lond). 2014 Oct;127(7):423-33. (PMID: 24963668)
Channels (Austin). 2015;9(6):336-43. (PMID: 26217968)
J Autoimmun. 2014 Dec;55:63-72. (PMID: 25175978)
J Clin Invest. 2008 Sep;118(9):3025-37. (PMID: 18688283)
J Invest Dermatol. 2017 Apr;137(4):801-804. (PMID: 28340683)
J Biol Chem. 1998 Aug 21;273(34):21542-53. (PMID: 9705284)
J Immunol. 2013 Dec 1;191(11):5371-82. (PMID: 24140646)
Drug Resist Updat. 2015 Jul-Aug;21-22:11-9. (PMID: 26183291)
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11651-6. (PMID: 9326665)
Pflugers Arch. 2015 Nov;467(11):2275-85. (PMID: 25715999)
Pharmaceuticals (Basel). 2016 Dec 14;9(4):. (PMID: 27983625)
PLoS One. 2014 Mar 14;9(3):e92013. (PMID: 24632741)
Expert Rev Clin Pharmacol. 2010 May;3(3):385-96. (PMID: 22111618)
J Crohns Colitis. 2014 Nov;8(11):1378-91. (PMID: 24793818)
Adv Wound Care (New Rochelle). 2015 Apr 1;4(4):213-224. (PMID: 25945284)
Br J Haematol. 2011 Apr;153(1):92-104. (PMID: 21323872)
J Anat. 2006 Feb;208(2):219-29. (PMID: 16441566)
J Invest Dermatol. 2014 Jun;134(6):1752-1754. (PMID: 24463422)
Cell. 2005 May 6;121(3):465-77. (PMID: 15882627)
Curr Neuropharmacol. 2018;16(5):618-626. (PMID: 28676010)
Pflugers Arch. 2009 Jun;458(2):291-302. (PMID: 19037656)
Annu Rev Immunol. 2015;33:291-353. (PMID: 25861976)
Transplantation. 2013 Jan 27;95(2):285-92. (PMID: 23325003)
Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):113-119. (PMID: 29050937)
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8151-6. (PMID: 10884437)
Ann Clin Transl Neurol. 2019 Mar 18;6(4):723-738. (PMID: 31019997)
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1541-6. (PMID: 20080610)
J Cardiovasc Pharmacol. 2013 Feb;61(2):102-12. (PMID: 23107876)
Pharmacol Rev. 2005 Dec;57(4):463-72. (PMID: 16382103)
Kidney Int. 2008 Sep;74(6):740-9. (PMID: 18547995)
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):E3225-34. (PMID: 23929777)
J Cereb Blood Flow Metab. 2016 Dec;36(12):2146-2161. (PMID: 26661208)
PLoS One. 2018 Jan 2;13(1):e0190307. (PMID: 29293584)
Cell Death Dis. 2013 Aug 15;4:e773. (PMID: 23949222)
Circ Res. 2006 Sep 1;99(5):537-44. (PMID: 16873714)
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14518-23. (PMID: 19706538)

UL1 TR001860 United States TR NCATS NIH HHS; R01 HL080173 United States HL NHLBI NIH HHS; P20 RR018751 United States RR NCRR NIH HHS; TL1 TR001861 United States TR NCATS NIH HHS; T32 GM099608 United States GM NIGMS NIH HHS

0 (Acetamides)
0 (Cytokines)
0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
0 (Kcnn4 protein, mouse)
0 (Trans-Activators)
0 (Trityl Compounds)
N12000U13O (Doxycycline)
TS6G201A6Q (senicapoc)

Date Created: 20200310 Date Completed: 20200527 Latest Revision: 20240423

20240423

PMC7062274

10.1371/journal.pone.0222619

32150577