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

• Applicant: Professor Dr. Triantafyllos Chavakis
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2011 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 189897882

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.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 252: Microenvironment of the Adrenal in Health and Disease