Claudin-1 decrease impacts epidermal barrier function in atopic dermatitis lesions dose-dependently
Sophia Bergmann, Barbara von Buenau, Sabine Vidal‐y‐Sy, Marek Haftek, Ewa Wladykowski, Pia Houdek, Susanne Lezius, Hélène Duplan, Katja Bäsler, Stephan Dähnhardt‐Pfeiffer, Christian Gorzelanny, Stefan W. Schneider, Elke Rodríguez, Dora Stölzl, Stephan Weidinger, Johanna M. Brandner
Abstract
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 inside-out 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.