The role of locally produced glucocorticoids in the skin in the regulation of immune responses and inflammation

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The skin, including its local immune system, provides an important barrier function, preventing potential pathogens from entering the body. However, uncontrolled immune responses in the skin may result in excessive, chronic and destructive inflammatory responses, as seen in allergies, atopic dermatitis and psoriasis. These inflammatory disorders are often treated with topical administration of immunosuppressive and anti-inflammatory glucocorticoids. Interestingly, the skin itself is capable of producing endogenous glucocorticoids, however the role of this local glucocorticoid production is at present incompletely understood. We hypothesize that local glucocorticoid synthesis in the skin is induced in response to local immune cell activation and tissue damage, and in turn contributes to the regulation of local inflammatory responses, such as atopic dermatitis. The aims of this study are therefore to characterize the local glucocorticoid synthesis in the skin under steady-state and inflammatory conditions, and to specifically assess the role of this local skin glucocorticoid synthesis in the regulation of skin immune responses and inflammation. Fur this purpose we have generated a conditional skin-specific knockout mouse with defective glucocorticoid synthesis in the skin. We will employ this mouse model to assess glucocorticoid synthesis, and changes in local immune responses and inflammation in experimental models of skin inflammation. Last but not least we aim to confirm the relevance of our results by analyzing skin biopsies from control and atopic dermatitis patients. The in-depth investigation of this research project will not only provide detailed insight into the regulation of glucocorticoid synthesis in the skin, and its role in the regulation of immune responses, but will also reveal whether defects of this local steroidogenesis could contribute to the development of inflammatory disorders of the skin in human patients. Last but not least it will investigate skin glucocorticoid synthesis as a potential therapeutic target for the treatment of inflammatory diseases of the skin and for the development of novel vaccinations.