Dissecting the adrenal-endothelial-immune interface in systemic inflammation: Implications for inflammationrelated adrenal dysfunction

在一个双向联系中，肾上腺功能可能受到炎症的损害，但也可能对全身炎症的结果产生关键影响。在第一个资助期，我们证明了内皮细胞Del-1，我们的实验室已经描述为白细胞募集的第一个内源性抑制剂，作为肾上腺炎症的看门人。在SIRS中，肾上腺中Del-1的下调促进了肾上腺功能障碍。据我们所知，这是第一个证明肾上腺内皮支持肾上腺稳态，对抗炎症相关的肾上腺功能障碍的研究。有趣的是，我们还发现具有免疫调节作用的肾上腺类固醇脱氢表雄酮可以刺激Del-1的表达。相反，近年来可能最突出的促炎细胞因子IL-17在肾上腺中强烈诱导sirs相关的肾上腺炎症并降低肾上腺Del-1的表达。我们将在这些发现的基础上进一步了解肾上腺类固醇（如皮质类固醇或脱氢表hea）、Del-1和IL-17之间的相互作用，在炎症依赖性肾上腺功能障碍中调节肾上腺-内皮-免疫界面。我们将使用不同的工具，如DHEA的应用，以及在SIRS/败血症小鼠模型中对IL-17/IL-17R轴进行药理学或遗传失活。这些实验将提高我们对炎症相关肾上腺功能障碍调节因素的认识，并为新的治疗方法提供基础。

In a bidirectional link, adrenal function may be compromised by inflammation but can also crucially affect the outcome of systemic inflammation. In the first funding period we demonstrated that endothelial Del-1, which our lab has described as the first endogenous inhibitor of leukocyte recruitment, acts as a gatekeeper of adrenal gland inflammation. In SIRS, adrenal downregulation of Del-1 promoted adrenal dysfunction. To our knowledge this was the first study demonstrating that adrenal endothelium supports adrenal homeostasis, counter-acting inflammation-related adrenal dysfunction. Interestingly, we also found the adrenal steroid DHEA, which has immune-modulatory actions, to stimulate Del-1 expression. On the contrary, the likely most prominent proinflammatory cytokine of recent years, IL-17, is strongly induced in the adrenal gland upon SIRS-related adrenal inflammation and decreases adrenal Del-1 expression. We will build upon these findings to understand further the crosstalk between adrenal steroids (such as corticosteroids or DHEA), Del-1 and IL-17 for regulating the adrenal-endothelial-immune interface in inflammation-dependent adrenal dysfunction. We will engage different tools, such as application of DHEA, as well as pharmacologic or genetic inactivation of the IL-17/IL-17R axis in mouse models of SIRS/sepsis. These experiments will improve our understanding of the factors regulating inflammation-related adrenal dysfunction and could provide the basis for new therapeutic approaches.