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Simple Summary Atopic dermatitis, also called neurodermatitis, is one of the best-known chronic inflammatory skin diseases with eczema, strong itch and dry skin. It is based on an impaired skin barrier with changes in the fats and proteins of the horny layer, which leads to a disturbed water balance. Prurigo nodularis is a less common and intractable chronic skin disease with very itchy nodules. It can be associated with atopic dermatitis (so called atopic prurigo) or with many other diseases. The aim of this study was to compare these three skin diseases classic atopic dermatitis, atopic prurigo and non-atopic prurigo nodularis with healthy control subjects with regard to their skin barrier. In all three disease groups, we then found marked disease severity, reduced water content and increased water loss through the skin, thickening and inflammation of the skin, altered levels of certain proteins and reduced fat layers, all of which demonstrate a severe disturbance of the skin barrier. The main therapeutic consequence is that basic barrier repair, as established for patients with atopic dermatitis in the form of consistent skincare, could also be crucial for patients with non-atopic prurigo nodularis due to this verified skin barrier damage. Abstract A deficient epidermal barrier is a key feature of atopic dermatitis (AD) and comprises altered lipid and protein content and composition of the stratum corneum resulting in disturbed water balance. Clinically, eczematous lesions on dry skin and pruritus develop. Pruritic nodules occur in prurigo nodularis (PN), another chronic skin disease, which can be associated with atopy. We aimed at comparing the three clinical pictures, classic AD, atopic prurigo (AP), and non-atopic PN, to healthy controls regarding the epidermal barrier. We determined clinical parameters and performed biophysical measurements, histology/immunohistochemistry, electron microscopy, and molecular biological analysis. We found distinctively elevated clinical scores, reduced hydration and increased transepidermal water loss, epidermal hyperplasia and inflammation reduced filaggrin and increased loricrin and involucrin expression, as well as reduced intercellular lipid lamellae in all three disease groups. These findings show a severe disruption in epidermal barrier structure and function in all three disorders so that epidermal barrier impairment is now proven not only for AD but also for PN.

E-cadherin controls a wide array of cellular behaviors, including cell-cell adhesion, differentiation, and tissue development. We show here that E-cadherin is cleaved specifically by ADAM (a disintegrin and metalloprotease) 10 in its ectodomain. Analysis of ADAM10-deficient fibroblasts, inhibitor studies, and RNA interference-mediated down-regulation of ADAM10 demonstrated that ADAM10 is responsible not only for the constitutive shedding but also for the regulated shedding of this adhesion molecule in fibroblasts and keratinocytes. ADAM10-mediated E-cadherin shedding affects epithelial cell-cell adhesion as well as cell migration. Furthermore, the shedding of E-cadherin by ADAM10 modulates the β-catenin subcellular localization and downstream signaling. ADAM10 overexpression in epithelial cells increased the expression of the β-catenin downstream gene cyclin D1 dose-dependently and enhanced cell proliferation. In ADAM10-deficient mouse embryos, the C-terminal E-cadherin fragment is not generated, and the full-length protein accumulates, highlighting the in vivo relevance for ADAM10 in E-cadherin shedding. Our data strongly suggest that this protease constitutes a major regulatory element for the multiple functions of E-cadherin under physiological as well as pathological conditions.