Reduced expression of epidermal growth factor receptor, E-cadherin, and occludin in the skin of flaky tail mice is due to filaggrin and loricrin deficiencies.
Disruption of skin barrier function leads to increases in the percutaneous transfer of allergens and the incidence of atopic dermatitis. Flaky tail (Flg(ft)) mice have been used as a model of atopic dermatitis with skin barrier dysfunction. Although Flg(ft) mice are known to have filaggrin mutation, the mechanism responsible for the skin barrier dysfunction that they display needs to be determined, especially for the roles of epidermal adhesion and junction proteins. Herein, we report the decreased expression of epidermal growth factor receptor (EGFR), E-cadherin, occludin, and SIRT1 in the skin of Flg(ft) mice, compared with those in C57BL/6J mice. Administration of N-acetyl-L-cysteine, an antioxidant, in the drinking water improved these protein expressions in the skin of Flg(ft) mice. Notably, we discovered that loricrin expression was suppressed in Flg(ft) mice. In vitro experiments showed that filaggrin small interfering RNA, loricrin small interfering RNA, or SIRT1 inhibitor sirtinol suppressed the expression levels of EGFR, E-cadherin, and occludin in a human immortalized keratinocyte cell line (HaCaT cells). Our findings suggest that the observed reductions in EGFR, E-cadherin, and occludin expression were due to filaggrin deficiency accompanied with subsequent loricrin deficiency and disruption of the SIRT1 pathway in the skin of Flg(ft) mice.
Department of Dermatology, Faculty of Medicine, Kagawa University, Japan. kozo@kms.ac.jp
Kozo
K
Nakai
Kozo
K
Yoneda
Yoichiro
Y
Hosokawa
Tetsuya
T
Moriue
Richard B
RB
Presland
Padraic G
PG
Fallon
Kenji
K
Kabashima
Hiroaki
H
Kosaka
Yasuo
Y
Kubota
D000111:Acetylcysteine / Q000494:pharmacology; D000388:Air; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D062793:Occludin; D034741:RNA, Small Interfering / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013623:Tail / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015820:Cadherins; D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D018836:Inflammation Mediators; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C064554:loricrin; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D056564:Sirtuin 1; D000111:Acetylcysteine