Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response.
Inflammatory skin disorders result in significant epidermal changes, including keratinocyte hyperproliferation, incomplete differentiation, and impaired barrier. Here we test whether, conversely, an impaired epidermal barrier can promote an inflammatory response. Mice lacking the transcription factor Kruppel-like factor 4 (Klf4) have a severe defect in epidermal barrier acquisition. Transcription profiling of Klf4(-/-) newborn skin revealed similar changes in gene expression to involved psoriatic plaques, including a significant upregulation of the gap junction protein connexin 26 (Cx26). Ectopic expression of Cx26 from the epidermis-specific involucrin (INV) promoter (INV-Cx26) demonstrated that downregulation of Cx26 is required for barrier acquisition during development. In juvenile and adult mice, persistent Cx26 expression kept wounded epidermis in a hyperproliferative state, blocked the transition to remodeling, and led to an infiltration of immune cells. Mechanistically, ectopic expression of Cx26 in keratinocytes resulted in increased ATP release, which delayed epidermal barrier recovery and promoted an inflammatory response in resident immune cells. These results provide a molecular link between barrier acquisition in utero and epidermal remodeling after wounding. More generally, these studies suggest that the most effective treatments for inflammatory skin disorders might concomitantly suppress the immune response and enhance epidermal differentiation to restore the barrier.
Djalilian
Ali R
AR
National Human Genome Research Institute, National Eye Institute, and National Institute of Child Health and Development, NIH, Bethesda, Maryland 20892, USA.
McGaughey
David
D
Patel
Satyakam
S
Seo
Eun Young
EY
Yang
Chenghua
C
Cheng
Jun
J
Tomic
Melanija
M
Sinha
Satrajit
S
Ishida-Yamamoto
Akemi
A
Segre
Julia A
JA
D000818:Animals; D000831:Animals, Newborn; D000072259:Connexin 26; D017630:Connexins / Q000502:physiology*; D004817:Epidermis / Q000276:immunology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007249:Inflammation; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics; D012871:Skin Diseases / Q000276:immunology / Q000473:pathology*; D014945:Wound Healing
D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D011498:Protein Precursors; D000072259:Connexin 26; C032253:involucrin