Project A01

Ferroptotic cell death in adrenal inflammation and septic shock

Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis significantly contributes to increased mortality in patients with sepsis. Recent studies have demonstrated the involvement of regulated necrosis (RN) and necroinflammation in sepsis-mediated multiorgan failure. It remains unknown whether induction of RN also contributes to sepsis-induced adrenal inflammation and dysfunction. In the previous funding period, we comprehensively analysed adrenal cell susceptibility to different forms of RN and found that human adrenocortical cells are particularly prone to iron-catalysed lipid peroxidation, known as ferroptosis. This finding aligns with recent in vivo evidence that iron overload is implicated in sepsis-induced organ damage. Furthermore, we found evidence of necroptosis induction in SARS-CoV-2-infected adrenal tissues from deceased COVID-19 patients. This suggests that RN induction in the adrenal gland may vary with the infecting microorganism and warrants further investigation. Notably, we found that steroidogenesis activation enhanced lipid peroxidation and sensitised adrenal cells to ferroptosis. Intriguingly, we also demonstrated that adrenal steroids can potentially promote ferroptosis in susceptible cells. These results indicate that ferroptosis may contribute to bacterial sepsis-induced adrenal gland dysfunction. To test this hypothesis in the final funding period, we will use genetic and pharmacological approaches. Specifically, we will use ferroptosis inhibitors and mice with adrenocortical cell-specific deletion of glutathione peroxidase 4 and Acyl-CoA synthetase long-chain family member 4 to evaluate the contribution of ferroptosis to LPS- and CLP-induced adrenal damage. Transgenic mice were successfully generated during the last funding period. In addition, we will use mouse and human spheroids to explore the modulatory effects of sex hormones, active steroidogenesis, and inflammatory cytokines on ferroptosis induction in primary adrenal cells. Furthermore, we will define the role of ferroptosis in our new mouse model of tuberculosis-induced primary adrenal insufficiency. The results of our study will provide valuable insights for upcoming clinical trials.

Aims:

(I) Study ferroptosis induction and define its role in sepsis-induced adrenal dysfunction.

(II) Characterize the regulatory mechanisms and effects of ferroptosis in primary adrenal cells.

(III) Define the role of ferroptosis in tuberculosis-induced adrenal insufficiency.

© SFB/TRR 205