The role of mast cells in skin barrier function

Terminal differentiation of epidermal keratinocytes establishes the stratum corneum, the skin`s outermost barrier against invasion of foreign antigens and microbes as well as against fluid loss from the inside. The formation of a regular skin barrier requires the concerted interaction of the epithelial and mesenchymal compartments of the skin i.e. epidermal and dermal cells through secreted factors and adhesion molecules. Atopic dermatitis and psoriasis are severe inflammatory skin diseases which affect up to 15% and 2-3% respectively of the general population and for which to date no curative treatment exists. Both diseases have in common pronounced alterations of the epidermal differentiation program leading to severe skin barrier function defects. These alterations are due to (1) inherited defects in the expression of differentiation-associated proteins and/or (2) the direct impact of inflammatory cells and their mediators on keratinocyte terminal differentiation and (3) a combination of the two mechanisms. Skin mast cells are situated within the dermis and participate in inflammatory reactions of the skin by release of soluble mediators, most prominently histamine, but also proteases and inflammatory and vasoactive cytokines. Increase of dermal mast cell numbers and mast cell activation is regularly seen in both, psoriasis and atopic dermatitis, and can be observed before the onset of visible skin alterations. The aim of the present project is to study the role of mast cells in inflammatory skin diseases with particular emphasis on their effect on the skin barrier formation. We will investigate in different in vitro and in vivo models (1) the influence of mast cell derived soluble mediators on the keratinocyte terminal differentiation program and on the skin barrier defect and (2) the consequence of epidermal barrier defects on mast cell function. The planned studies will contribute to a better understanding of the role of mast cells in the initiation and perpetuation of inflammatory skin diseases with skin barrier defects and will help to identify targets for their treatment and prevention.

During their differentiation process skin cells (keratinocytes) form the outermost barrier of the skin the stratum corneum which prevents entry of foreign antigens and microbes as well as fluid loss from the inside. For the establishment of an intact skin barrier the interaction between keratinocytes in the upper skin layer (epidermis) and other cells in the lower skin layer (dermis) is of importance. One central cell type in the dermis the mast cell was shown to be increased in numbers in diseases such as atopic dermatitis, where skin barrier defects are regularly observed.In our study we demonstrated that mast cells, by releasing their main mediator histamine, block the differentiation of keratinocytes resulting in a defective outer skin barrier. In response to histamine, keratinocytes cannot form as tight cell contacts as needed due to lower production of very important structural proteins. We used different models to show this influence of histamine on the skin barrier: artificial skin cultured in the laboratory and a mouse model. Importantly, our results are also of clinical relevance, since we could show that antihistamines nowadays mainly used for the treatment of allergies can diminish the destruction of the skin barrier. Based on this finding, our study re-initiated discussions about the potential benefit of antihistamines in atopic diseases. The exciting results of this first study prompted us to search for other important mediators released from mast cells that potentially influence skin function. For this approach mast cells were isolated from human skin and analyzed by a novel technique proteomics which allows the identification of all proteins present in a cell. Furthermore, this method allows comparison to other skin cells and thereby led to the identification of two novel mast cell proteins. Further studies investigating the role of these two proteins in the skin are planned.