Changes in connexin 43 in inflammatory skin disorders: Eczema, psoriasis, and Steven-Johnson syndrome/toxic epidermal necrolysis

Abstract

Background: Connexin 43 (Cx43) plays a central role in the inflammatory response and wound healing. Targeting Cx43 expression reduces inflammation in a variety of injuries. The expression pattern of Cx43 has not been described for many inflammatory skin diseases.

Objectives: To describe the expression patterns of Cx43 in eczema, psoriasis, Steven-Johnson syndrome/toxic epidermal necrolysis.

Methods: Archival skin biopsies from patients with eczema, psoriasis, and Steven-Johnson syndrome/toxic epidermal necrosis were identified and examined, with sister sections stained for Cx43 and imaged by confocal microscopy. All samples were compared to age and site-matched normal skin controls.

Results: Epidermal Cx43 is reduced in acute eczema, absent in regions of spongiosis, and is highly elevated in subacute and chronic eczema. In plaque psoriasis, Cx43 is overexpressed in areas with psoriasiform hyperplasia with a fish-scale-like appearance but is lost in regions surrounding neutrophil microabscesses. Cx43 staining is strong in the neutrophils within these microabscesses. In SJS/TEN, Cx43 expression is elevated in areas bordering normal tissue but is rapidly lost in areas of keratinocyte necrosis.

Conclusions: Dynamic changes in Cx43 levels are seen in inflammatory skin diseases and may represent future potential therapeutic targets.

Keywords: dermatitis; epidermal necrosis; expression patterns; gap junction; psoriasiform.

FIGURE 1

Downregulation of Cx43 expression in the spongiotic epidermis of eczema patients. Representative images of Cx43 staining of skin biopsy samples from normal skin (F) as well as patients with acute eczema (G, H; subject E10), subacute eczema (I; subject E6), and chronic eczema (J, subject E9). Corresponding H&E images of Cx43 staining (A‐E). Scale bars = 50 μm, 40× images. Dotted line marks the outline between the epidermis and dermis. Cx43 staining was visibly reduced in spongiotic areas, which are more commonly found in acute eczema samples. In subacute and chronic eczema samples Cx43 staining was closer to normal Cx43 expression shown in control skin except in regions where spongiosis could be observed

FIGURE 2

Upregulation of Cx43 in intraepidermal neutrophilic abscesses and downregulation in surrounding epidermis of patients with psoriasis. Representative images of Cx43 staining of skin biopsy samples from normal skin (D) as well as patients with psoriasis either in the absence of neutrophilic abscess (E; subject P6) or in the presence of neutrophilic abscesses (F; subject P4). Corresponding H&E images of Cx43 staining (A‐C). Red circle marks areas of neutrophilic abscess. Dotted line marks the outline between the epidermis and dermis. Scale bars = 50 μm. In the absence of neutrophilic abscesses, Cx43 appears to be upregulated in the spinous to granular layer forming linear arrays of gap junction plaques compared to normal punctate staining shown in control skin. With the appearance of neutrophilic abscesses, Cx43 expression is found in the neutrophils, however Cx43 downregulation was observed in the surrounding epidermis

FIGURE 3

Change in Cx43 expression in patients with SJS/TEN. Representative images of Cx43 staining of skin biopsy samples from normal skin (G) and patients with SJS or SJS/TEN overlap showing mild focal keratinocyte necrosis (H, I; from subject S8), patchy areas of keratinocyte necrosis (J; from subject S1), widespread keratinocyte necrosis (K; from subject S10), and pan‐epidermal necrosis (L; from subject S5). Corresponding H&E images of Cx43 staining (A‐F). Arrows mark infiltration of leucocytes. White and red dotted line marks the epidermis and dermis, respectively. Scale bars = 50 μm, 40× images. Cx43 expression is elevated in the epidermis showing focal keratinocyte necrosis. As the keratinocyte necrosis becomes more widespread in the epidermis, Cx43 expression becomes cytoplasmic compared to normal punctate staining in control skin. In the sections showing pan‐epidermal necrosis Cx43 expression is lost at areas of epidermal detachment