TY - JOUR
T1 - Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death
AU - Kapralov, Alexandr A.
AU - Yang, Qin
AU - Dar, Haider H.
AU - Tyurina, Yulia Y.
AU - Anthonymuthu, Tamil S.
AU - Kim, Rina
AU - St. Croix, Claudette M.
AU - Mikulska-Ruminska, Karolina
AU - Liu, Bing
AU - Shrivastava, Indira H.
AU - Tyurin, Vladimir A.
AU - Ting, Hsiu Chi
AU - Wu, Yijen L.
AU - Gao, Yuan
AU - Shurin, Galina V.
AU - Artyukhova, Margarita A.
AU - Ponomareva, Liubov A.
AU - Timashev, Peter S.
AU - Domingues, Rosario M.
AU - Stoyanovsky, Detcho A.
AU - Greenberger, Joel S.
AU - Mallampalli, Rama K.
AU - Bahar, Ivet
AU - Gabrilovich, Dmitry I.
AU - Bayır, Hülya
AU - Kagan, Valerian E.
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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)/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 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.
AB - 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)/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 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.
UR - https://www.scopus.com/pages/publications/85079810992
U2 - 10.1038/s41589-019-0462-8
DO - 10.1038/s41589-019-0462-8
M3 - Article
C2 - 32080625
AN - SCOPUS:85079810992
SN - 1552-4450
VL - 16
SP - 278
EP - 290
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 3
ER -