Membranes Seminar

Please sign up for a sandwich no later than 24 February at 12:00 at: https://events.au.dk/membrsem2802/signup

Abstract

In this presentation, I will introduce the major forms of regulated cell death, mainly ferroptosis and necroptosis, and discuss novel data on the regulation of inflammation by necrotic cells (necroinflam-mation). In addition, immunosuppressive agents, such as dexamethasone, may directly affect cell death. Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treat-ment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalysed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dex-amethasone. Mechanistically, we identified that dexamethasone upregulated the GSH metabolism regu-lating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1-knock-down reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis-inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced in-crease in tubular necrosis in freshly-isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase of DPEP1-expression and GSH-depletion. Together, we identified a novel mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.

Host: Ina Maria Schiessl

On behalf of the organizer
Søren Brandt Poulsen
Administrative Research Theme Coordinator
MEMBRANES