ADAM10-Mediated E-Cadherin Release Is Regulated by Proinflammatory Cytokines and Modulates Keratinocyte Cohesion in Eczematous Dermatitis

Abstract

Acute eczema is an inflammatory skin disease characterized by the formation of small intraepidermal blisters, reduction of the adhesion molecule E-cadherin from the keratinocyte surface, and impaired keratinocyte cohesion. Here, we reveal that the disintegrin and metalloprotease ADAM10 is critically involved in regulating E-cadherin cell-surface expression in cultured primary human keratinocytes and in diseased human skin. Proinflammatory cytokines, transforming growth factor-beta, and lipopolysaccharide led to increased release of soluble E-cadherin by activating mitogen-activated protein kinase signaling in cultured keratinocytes. Moreover, these stimuli decreased the amount of pro-ADAM10 and increased the level of the active protease, leading to loss of E-cadherin from the cell surface and decreased keratinocyte cohesion. In situ examination and immunoblot analyses of E-cadherin and ADAM10 expression in lesional skin of eczema revealed that the reduction of E-cadherin expression in areas of blister formation closely correlated with increased level of ADAM10 expression and elevated E-cadherin shedding. Our data suggest that ADAM10-mediated E-cadherin proteolysis leads to the impaired cohesion of keratinocytes observed in eczematous dermatitis and provide previously unreported insights into the understanding of the molecular mechanisms involved in inflammatory diseases with loss in epithelial integrity.

The disintegrin/metalloproteinase Adam10 is essential for epidermal integrity and Notch-mediated signaling

“…This in turn may alter the microenvironment, resulting in recruitment and activation of immune cells, and further aggravation of the phenotypes, as has been described for loss of Notch function in the skin (Demehri et al, 2008;Dumortier et al, 2010). Interestingly, overexpression or increased activation of Adam10 in humans has been associated with oncogenesis and chronic skin diseases such as psoriasis and eczema (Dittmer et al, 2009;Lee et al, 2010;Maretzky et al, 2008;Oh et al, 2008). As the inducible Notch1 mutants also showed increased susceptibility for spontaneous and chemically induced skin carcinogenesis Nicolas et al, 2003), it would be of great interest to examine a potential tumor suppressive effect of Adam10 in the skin.…”

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

“…Additional markers of epidermal differentiation, including loricrin and keratin-10 (K10), responded similarly to Erbin knockdown, demonstrating reduced protein expression ( Figure 3B and Supplemental Figure 1B). Erbin knockdown did not affect expression levels of keratin-5 (K5), a marker of basal keratinocytes, or E-cadherin, a core adherens junction component expressed throughout the epidermis (49). Erbin siRNA-1 was the primary reagent used for knockdown and is referred to here and in the figures simply as Erbin siRNA.…”

Quantitative and dynamic expression profile of premature and active forms of the regional ADAM proteins during chicken brain development

“…ADAM10 can shed different substrates such as amyloid precursor protein (APP), Notch and its ligand Delta 1, HB-EGF, EGF receptor, and cadherins including E-cadherin, N-cadherin, protocadherin C3 and VE-cadherin. All of them are involved in embryonic development [12,16,[42][43][44][45][46][47][48]. Therefore, the spatial and temporal regulation of the active form of the ADAM10 protein suggests a role of ADAM10 in development of the embryonic brain.…”