Interdependencies between Inflammatory Processes and Barrier Lipids in Diseased Skin
Dermatology
Final Report Abstract
The general aim of the proposed joint project was to gain a more fundamental understanding of the physiological processes leading to a competent skin barrier and disturbances of these processes in inflammatory skin diseases such as atopic dermatitis (AD). In the first part of the project, we investigated the impact of normal and AD patientderived fibroblasts on skin homeostasis,their interplay with T cells and effects on the organization of skin barrier and skin lipids. Interestingly, we identified different subsets of fibroblasts isolated from AD patients triggeringan atopic phenotype as well as inflammatory processes in the skin models. Although the underlying mechanism still need to be identified, our results indicate an involvement of the differentiation factor LIF. In a second subproject, we investigate the development of skin equivalents without the presence of fibroblasts. We observed significant differences in the differentiation and maturation as determined by a time-course measurement resulting in significantly impaired skin barrier function in the skin models without fibroblasts. Hightroughput western blot analysis also showed that Ras/Raf/MEK/ERK singaling was significantly altered in the models without fibroblasts. Finally, we develped a novel method for the preparation of a dermis equivalent by self-assembly of fibroblasts and endothelial cells and endogenoeus extracellular matrix (ECM) production. Skin equivalents generated using these self-asembled matrices showed a significantly improved differentiation and more physiological expression of skin barrier lipids and tight junction proteins indicative for the pivotal role of ECM for tissue homeostasis. Future studies aim to identify the mediators of cellular crosstalk in healthy and diseased skin and will also include an approach to stratify atopic dermatitis patients depending on their fibroblast activity.
