Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death.
Nat Chem Biol
; 16(3): 278-290, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-32080625
ABSTRACT
Ferroptotic death is the penalty for losing control over three processes-iron metabolism, lipid peroxidation and thiol regulation-that are common in the pro-inflammatory environment where professional phagocytes fulfill their functions and yet survive. We hypothesized that redox reprogramming of 15-lipoxygenase (15-LOX) during the generation of pro-ferroptotic signal 15-hydroperoxy-eicosa-tetra-enoyl-phosphatidylethanolamine (15-HpETE-PE) modulates ferroptotic endurance. Here, we have discovered that inducible nitric oxide synthase (iNOS)/NOâ¢-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 phagocytes, in comparison to M2 phagocytes, exert higher resistance to pharmacologically induced ferroptosis. This resistance is diminished in iNOS-deficient cells in the pro-inflammatory conditions of brain trauma or the tumour microenvironment. The nitroxygenation of eicosatetraenoyl (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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Óxido Nítrico Sintase Tipo II
/
Ferroptose
/
Macrófagos
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article