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

皮肤，包括其局部免疫系统，提供了重要的屏障功能，防止潜在的病原体进入体内。然而，皮肤中不受控制的免疫反应可能导致过度的、慢性的和破坏性的炎症反应，如在过敏、特应性皮炎和牛皮癣中所见。这些炎性疾病通常通过局部施用免疫抑制和抗炎糖皮质激素来治疗。有趣的是，皮肤本身能够产生内源性糖皮质激素，然而这种局部糖皮质激素产生的作用目前还不完全清楚。我们假设皮肤中的局部糖皮质激素合成是响应于局部免疫细胞活化和组织损伤而诱导的，并且反过来有助于调节局部炎症反应，例如特应性皮炎。因此，本研究的目的是表征稳态和炎症条件下皮肤中的局部糖皮质激素合成，并具体评估这种局部皮肤糖皮质激素合成在皮肤免疫反应和炎症调节中的作用。为此目的，我们已经产生了皮肤中糖皮质激素合成缺陷的条件性皮肤特异性敲除小鼠。我们将使用这种小鼠模型来评估糖皮质激素的合成，以及皮肤炎症实验模型中局部免疫反应和炎症的变化。最后但并非最不重要的是，我们的目标是通过分析对照组和特应性皮炎患者的皮肤活检来确认我们结果的相关性。该研究项目的深入调查不仅将提供对皮肤中糖皮质激素合成的调节及其在免疫反应调节中的作用的详细见解，而且还将揭示这种局部类固醇合成的缺陷是否会导致人类患者皮肤炎症性疾病的发展。最后但并非最不重要的是，它将研究皮肤糖皮质激素合成作为治疗皮肤炎性疾病和开发新型疫苗的潜在治疗靶点。

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.