Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response
Ali R. Djalilian, David McGaughey, Satyakam Patel, Eun Young Seo, Chenghua Yang, Jun Cheng, Melanija Tomic, Satrajit Sinha, Akemi Ishida-Yamamoto, Julia A. Segre
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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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 4

Histology of homozygous Inv-Cx26 mice with hyperkeratosis, hyperproliferation, increased number of gap junctions, and enhanced in vivo dye transfer.

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Histology of homozygous Inv-Cx26 mice with hyperkeratosis, hyperprolifer...
(A and B) Histology of homozygous Inv-Cx26 skin reveals increased number of spinous cell layers with more compact stratum corneum. The dotted lines mark basement membrane. (C–F) Hyperproliferation in homozygous Inv-Cx26 mice with upregulation of K6 suprabasally and increased number of BrdU-positive cells. The dotted or α6-stained red lines mark basement membrane. (G and H) Increased gap junctions in homozygous Inv-Cx26 skin. Arrows indicate gap junctions. d, desmosomes. (I and J) In vivo dye transfer experiments with neurobiotin (green) and rhodamine dextran (red) demonstrated increased junctional communication in homozygous Inv-Cx26 skin. The white bracket marks the wound incision. Only 1 side of wound is shown. Magnification, ×40 (A–F), ×10 (I and J). Scale bars: 100 nm (G and H).