Immune mechanisms and potential therapeutic interventions for sepsis-induced adrenal gland inflammation

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Systemic inflammation resulting from infections frequently culminates in fatal septic shock syndrome. An adequate adrenal stress response is critical to cope with this life-threatening situation. In many critically ill patients, this homeostatic activation of the adrenal gland hormone production is impaired, although the mechanisms are mostly unknown. In the previous funding period, we demonstrated that both endotoxemiaprovoked SIRS and cecal ligation and puncture (CLP)-induced sepsis lead to systemic and adrenal gland inflammation which was associated with rapid immune cell infiltration and onset of cellular death of adrenal cells. Furthermore, we engaged mice with tissue-specific inactivation of TLR signaling, enabling us to identify myeloid cells in the adrenal gland microenvironment as being crucially involved in hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal inflammation. In the next funding period we plan to further study the importance of tissue-restricted TLR signaling, immune cell infiltration, mitochondria function and dysfunction in the adrenal gland inflammation and cell death. Finally, we will study the protective effect of novel anti-inflammatory and mitochondria-targeted therapeutic interventions in the resolution of adrenal inflammation and prevention of cell death. With these approaches we will better understand the underlying mechanisms involved in sepsis-mediated adrenal gland deregulation and identify novel therapeutic interventions in sepsis treatments.