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

皮肤，包括它的局部免疫系统，提供了一个重要的屏障功能，防止潜在的病原体进入人体。然而，皮肤中不受控制的免疫反应可能会导致过度的、慢性的和破坏性的炎症反应，如过敏、特应性皮炎和牛皮癣。这些炎症性疾病通常通过局部应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。我们假设皮肤中局部糖皮质激素的合成是在局部免疫细胞激活和组织损伤的反应下诱导的，反过来又有助于调节局部炎症反应，如特应性皮炎。因此，这项研究的目的是描述稳态和炎症条件下皮肤局部糖皮质激素合成的特征，并具体评估这种局部皮肤糖皮质激素合成在调节皮肤免疫反应和炎症中的作用。出于这个目的，我们创造了一种皮肤特异的条件性基因敲除小鼠，其皮肤中的糖皮质激素合成存在缺陷。我们将使用这个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。最后但同样重要的是，我们的目标是通过分析对照和特应性皮炎患者的皮肤活检来确认我们的结果的相关性。最后但同样重要的是，它将研究皮肤糖皮质激素的合成，将其作为治疗皮肤炎症性疾病和开发新型疫苗的潜在治疗目标。

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.