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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Research Article Dermatology

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 6

Heterozygous Inv-Cx26 mice reepithelialize wounds but fail to remodel and heal the wounds.

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Heterozygous Inv-Cx26 mice reepithelialize wounds but fail to remodel an...
(A) Gross appearance of 5-mm punch biopsy wound healing in wild-type control and heterozygous Inv-Cx26 mice over time. (B) Histology at 7, 14, and 21 days after wounding of heterozygous Inv-Cx26 mice. (C) Higher magnification of heterozygous Inv-Cx26 skin demonstrates hypogranulosis and parakeratosis. (D) Expression of CX26 protein 7 and 21 days after wounding on wild-type and heterozygous Inv-Cx26 mice. In control wounded skin, Cx26 is expressed in wound edge migrating epidermis but was undetectable after wound closure and remodeling. The heterozygous Inv-Cx26 epidermis retained CX26 expression even after reepithelialization. Basement membrane is marked by the dashed white line. (E) Heterozygous Inv-Cx26 epidermis remains hyperproliferative, as demonstrated by BrdU staining, even after reepithelialization. BrdU-positive cells were found in the basal layer. Basement membrane is marked by the dashed black line. Magnification, ×10 (B), ×40 (C–E).