Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response
Ali R. Djalilian, … , Akemi Ishida-Yamamoto, Julia A. Segre
Ali R. Djalilian, … , Akemi Ishida-Yamamoto, Julia A. Segre
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1243-1253. https://doi.org/10.1172/JCI27186.
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Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response

Abstract

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.

Authors

Ali R. Djalilian, David McGaughey, Satyakam Patel, Eun Young Seo, Chenghua Yang, Jun Cheng, Melanija Tomic, Satrajit Sinha, Akemi Ishida-Yamamoto, Julia A. Segre

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Figure 1

KLF4 regulates Cx26 transcription levels by binding directly to the proximal promoter.

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KLF4 regulates Cx26 transcription levels by binding directly to the prox...
(A) Levels of Cx26 mRNA are relative to Klf4 expression. At E16.5, when the epidermal permeability barrier was first established, Klf4–/– and K5-Klf4 transgenic mice express 3.0-fold higher and 1.6-fold lower levels of Cx26 mRNA than wild-type littermates, respectively. The upregulation of Cx26 persists in Klf4–/– mice at E18.5 and as newborns (NB). (B) CX26 protein is weakly expressed in the suprabasal layers of newborn wild-type skin and strongly expressed in Klf4–/– epidermis. Basement membrane (BM) is marked with α6 integrin staining. Magnification, ×40. (C) KLF4 protein represses minimal Cx26 promoter in a dose-dependent manner. Cx26 promoter (Cx26p) yields activation 8-fold greater than promoterless pGL3 vector. This activity is repressed in a dose-dependent fashion by cotransfection with Klf4. (D) KLF4 binds sequences in the proximal Cx26 promoter. Computational analysis predicted 2 KLF4 binding sites in the minimal Cx26 promoter. As shown by EMSA, both sites are bound by KLF4. +, positive control for KLF4 binding site; –, mutated KLF4 site. (E) KLF4 binds directly to the proximal Cx26 promoter. Quantitative real-time PCR performed on specific KLF4 chromatin immunocomplexes demonstrated that the Cx26 promoter region is enriched 3.7-fold relative to an amplicon 5 kb proximal to the Cx26 locus. Results for all samples are normalized to input DNA.