Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death

Abstract

Ferroptotic death is the penalty for lost control over three processes – iron metabolism, lipid peroxidation and thiol regulation – common for pro-inflammatory environment where professional phagocytes fulfill their functions yet survive. We hypothesized that redox reprogramming of 15-lipoxygenase (15-LOX) during generation of pro-ferroptotic signals, 15-hydroperoxy-eicosa-tetra-enoyl-phosphatidylethanolamine (15-HpETE-PE), modulates the ferroptotic endurance. Here, we discovered that iNOS/NO•-enrichment of activated M1 (but not alternatively activated M2) macrophages/microglia modulates susceptibility to ferroptosis. Genetic or pharmacologic depletion/inactivation of iNOS confers sensitivity on M1 cells whereas NO• donors empower resistance of M2 cells to ferroptosis. In vivo , M1 (vs M2) phagocytes exert higher resistance to pharmacologically induced ferroptosis; this resistance is diminished in iNOS-deficient cells in pro-inflammatory conditions of brain trauma or tumor microenvironment. The nitroxygenation of ETE-PE intermediates and oxidatively-truncated species by NO• donors and/or suppression of NO• production by iNOS inhibitors represent a novel redox mechanism of regulation of ferroptosis in pro-inflammatory conditions.