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 2

Molecular characterization of the Inv-Cx26 transgenic mice.

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Molecular characterization of the Inv-Cx26 transgenic mice. (A) Schemati...
(A) Schematic representation of the Inv-Cx26 transgene. The complete murine Cx26 cDNA sequence was cloned downstream of the Inv regulatory sequences. (B) Genotyping of transgenic mice by interphase FISH with distinct chromosomal insertion sites (representative data for 1 line). Metaphase FISH was used for all further studies to genotype littermates resulting from crossing 2 heterozygous (Het) mice: heterozygous transgenic mice (1 hybridization signal) and homozygous (Homo) transgenic mice (2 hybridization signals). (C) CX26 immunohistochemistry demonstrated expression in the suprabasal layer of newborn heterozygous and homozygous Inv-Cx26 transgenic mouse skin at the membrane (inset: confocal image). (D) Expression levels of transgenic and endogenous (endo) Cx26 mRNA in 3 different lines of Inv-Cx26 mice, both heterozygotes (L, K, and F) and homozygotes (L/L and K/K). (E) Expression of CX26 protein in heterozygous and homozygous Inv-Cx26 mice. Homozygote L/L and K/K Inv-Cx26 mice expressed twice as much protein as their respective heterozygote L and K littermates. Magnification, ×100 (B, inset C), ×40 (C).