The transmembrane protein claudin-1 is a major component of epidermal tight junctions (TJs), which create a dynamic paracellular barrier in the epidermis. Claudin-1 downregulation has been linked to atopic dermatitis (AD) pathogenesis but variable levels of claudin-1 have also been observed in healthy skin. To elucidate the impact of different levels of claudin-1 in healthy and diseased skin we determined claudin-1 levels in AD patients and controls and correlated them to TJ and skin barrier function. We observed a strikingly broad range of claudin-1 levels with stable TJ and overall skin barrier function in healthy and non-lesional skin. However, a significant decrease in TJ barrier function was detected in lesional AD skin where claudin-1 levels were further reduced. Investigations on reconstructed human epidermis expressing different levels of claudin-1 revealed that claudin-1 levels correlated with insideout and outside-in barrier function, with a higher coherence for smaller molecular tracers. Claudin-1 decrease induced keratinocyte-autonomous IL-1β expression and fostered inflammatory epidermal responses to non-pathogenic Staphylococci. In conclusion, claudin-1 decrease beyond a threshold level results in TJ and epidermal barrier function impairment and induces inflammation in human epidermis. Increasing claudin-1 levels might improve barrier function and decrease inflammation and therefore be a target for AD treatment. Tight junctions (TJs) are an important component of the complex epidermal barrier system. They are localized in the stratum granulosum (SG) of the epidermis and provide mechanical barrier function to ions and solutes of different molecular sizes 1-4. The transmembrane protein claudin-1 (Cldn-1) is a major component of TJs 5. It is also found outside of TJs in basal and suprabasal layers of the epidermis 2,5. Mice with a complete Cldn-1 knockout (KO) die at the first day of birth due to increased transepidermal water loss (TEWL) 5. They develop TJs leaky to a molecular tracer (Biotin-556) 5 , and a highly water permeable stratum corneum (SC) 6. Human subjects lacking Cldn-1 suffer from the Neonatal Ichthyosis-Sclerosing Cholangitis (NISCH) syndrome which includes an ichthyosiform skin phenotype 7. An archetypical disease of epidermal barrier dysfunction is atopic dermatitis (AD) 8. Cldn-1 single nucleotide polymorphisms were linked to AD in some cohorts 9-11 , but not in others 11,12. Using immunostaining-intensity measurements and western blot analyses, reduced Cldn-1 levels were found in lesional AD skin 13-16. For non-lesional skin, divergent observations were described. Some authors found decreased mRNA and immunointensity levels 10 , while others observed no alteration of Cldn-1 immunointensity and western-blot levels 14,16 .
Background: Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity. Objectives: We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD. Methods: We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings. Results: Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, T H 1, T H 2, and T H 17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of T H 1, T H 2, and T H 17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator. Conclusions: Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened T H 2, T H 1, T H 17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting. (J
Background The Atopic Dermatitis (AD) TREATgermany registry was initiated by the German Society for Dermatology (DDG) in 2011 to evaluate the 'real-life' situation of health care for patients with AD.
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