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.

Cx26 regulates proliferation of repairing basal airway epithelial cells

“…It was suggested that persistent expression of Cx26 in suprabasal cells, by virtue of the involucrin promoter, maintained the epidermis in a hyperproliferative state (Djalilian et al, 2006), suggesting that Cx26 stimulated proliferation. This scenario was not supported in a recent study reporting that ectopic expression of Cx26 in basal keratinocytes using the CK5 promoter showed a tendency to decrease proliferation but had no pathological skin alteration as compared to control mice (Wang et al, 2010).…”

“…Cx26 is expressed in proliferative epidermis during early embryonic development but inhibited at terminal differentiation (Goliger, Paul, 1994;Choudhry et al, 1997). Moreover, mice lacking the Krüppel-like transcription factor 4 gene (klf4), which is known to act as an antiproliferative gene (McConnel, Yang, 2010), showed severe defects in epidermal barrier acquisition with keratinocyte hyperproliferation and lesions characteristic of psoriasis (Segre Bauer, Fuchs, 1999;Djalilian et al, 2006). Interestingly, KLF4 was found to bind directly to the Cx26 promoter and repress its transcription, suggesting that enhanced keratinocyte proliferation in Klf4 -/-mice is linked to Cx26 expression (Djalilian et al, 2006).…”

“…Moreover, mice lacking the Krüppel-like transcription factor 4 gene (klf4), which is known to act as an antiproliferative gene (McConnel, Yang, 2010), showed severe defects in epidermal barrier acquisition with keratinocyte hyperproliferation and lesions characteristic of psoriasis (Segre Bauer, Fuchs, 1999;Djalilian et al, 2006). Interestingly, KLF4 was found to bind directly to the Cx26 promoter and repress its transcription, suggesting that enhanced keratinocyte proliferation in Klf4 -/-mice is linked to Cx26 expression (Djalilian et al, 2006). Few studies have investigated KLF4 in the respiratory system and the information available has been obtained in developmental and morphogenesis studies (Wani, Wert, Lingrel, 1999;Cowan et 5 al., 2010).…”

Defective channels lead to an impaired skin barrier

“…Gap junctions are major channels that allow cells to communicate with one another by facilitating intercellular communication, including the transfer of Ca 2+ , a fundamental ion in keratinocyte differentiation, and small molecules of ,1 kDa -such as inositol triphosphate (IP 3 ) -between cells. In the skin, gap junctions appear to regulate a number of cellular processes, including wound healing, differentiation and barrier function (Goliger and Paul, 1995;Coutinho et al, 2003;Qiu et al, 2003;Djalilian et al, 2006;Mori et al, 2006;Man et al, 2007;Kandyba et al, 2008;Simpson et al, 2013), and their role in epidermal integrity is reviewed elsewhere (Martin et al, 2014).…”

Misbehaving macrophages in the pathogenesis of psoriasis

“…Mice with this defect develop inflammatory lesions within the skin that have many similarities to the histologic changes seen in psoriasis (10). Proponents of these models argue that the intrinsic defect in psoriasis may well lie within the skin and, more specifically, that psoriatic skin cells may overproduce inflammatory mediators that can engender and perpetuate inflammatory reactions independent of the action of autoreactive T cells (13).…”