The role of mast cells in skin homeostasis and inflammation

Mast cells are central immune cells in the skin located in the dermis in close proximity to the epidermis, nerves and blood vessels. Therefore, mast cells have the possibility to interact with many other cell types present in the skin either by direct contract or via the secretion of soluble mediators. In a previous study we could show one example for such an interaction via the secretion of the allergy-mediator histamine. Histamine released from mast cells binds its receptor on epidermal cells (keratinocytes) and inhibits the production of important structural proteins in these cells. Due to the lack of these proteins keratinocytes cannot build tight cell-cell contacts resulting in a disturbed barrier function of the skin. Consequences of a defective skin barrier are dry skin and also serious illnesses like atopic dermatitis. In the planned study we want to investigate how exactly histamine influences skin barrier function, i.e. what happens after histamine binds its receptor on keratinocytes. In a first step we will analyze a wide variety of different signaling pathways followed by experiments investigating single promising factors showing their role in histamine-induced barrier malfunction. The identification of the factors responsible for the histamine-induced skin barrier destruction might be important for the development of new therapies preventing skin barrier defects in atopic dermatitis. In another part of the study we intend to identify other as yet undescribed mast cell proteins that are important for the interaction of mast cells with other cells in the skin. To achieve this goal we performed a transcriptome- and proteome-analysis, i.e. we analyzed the entirety of all substances produced in mast cells. Based on this pool of data we already identified two novel mast cell proteins and in the current study we intend to analyze three other new mast cell proteins. Further characterization of these proteins will be based on the confirmation of their expression in cultured mast cells as well as in mast cells in healthy and diseased skin. Additional experiments concerning the functions of these novel proteins will be performed in a human skin equivalent model with special emphasis on their interaction with other skin cells. Together both planned subprojects will be of value for the better understanding of mast cells and their functions in healthy skin as well as in skin diseases such as atopic dermatitis.