Dataset Information

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

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)/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.

SUBMITTER: Kapralov AA

PROVIDER: S-EPMC7233108 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kapralov Alexandr A AA Yang Qin Q Dar Haider H HH Tyurina Yulia Y YY Anthonymuthu Tamil S TS Kim Rina R St Croix Claudette M CM Mikulska-Ruminska Karolina K Liu Bing B Shrivastava Indira H IH Tyurin Vladimir A VA Ting Hsiu-Chi HC Wu Yijen L YL Gao Yuan Y Shurin Galina V GV Artyukhova Margarita A MA Ponomareva Liubov A LA Timashev Peter S PS Domingues Rosario M RM Stoyanovsky Detcho A DA Greenberger Joel S JS Mallampalli Rama K RK Bahar Ivet I Gabrilovich Dmitry I DI Bayır Hülya H Kagan Valerian E VE

Nature chemical biology 20200217 3

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 ...[more]

PMID: 32080625

Similar Datasets

Project description:BackgroundDespite an increasing understanding of chronic obstructive pulmonary disease (COPD) pathogenesis, the mechanisms of diverse cell populations in the human lung remain unknown. Using single-cell RNA sequencing (scRNA-Seq), we can reveal changes within individual cell populations in COPD that are important for disease pathogenesis and characteristics.MethodsWe performed scRNA-Seq on lung tissue obtained from donors with non-COPD and mild-to-moderate COPD to identify disease-related genes within different cell types. We testified the findings using qRT-PCR, immunohistochemistry, immunofluorescence and Western blotting from 25 additional subjects and RAW 264.7 macrophages. Targeting ferroptosis with the ferroptosis inhibitor ferrostatin-1, iron chelator deferoxamine or HO-1 inhibitor zinc protoporphyrin was administered in the experimental cigarette smoke COPD mouse model.ResultsWe identified two populations of alveolar macrophages (AMs) in the human lung that were dysregulated in COPD patients. We discovered that M2-like AMs modulate susceptibility to ferroptosis by disrupting lipid and iron homeostasis both in vivo and in vitro. The discrepancy in sensitivity to ferroptosis can be determined and regulated by HO-1. In contrast, M1-like AMs showed the ability to attenuate oxidative stress and exert resistance to ferroptosis. In addition, the expression of genes within M2-like AMs is also involved in defects in phagocytosis and lysosome distortion. This ferroptotic phenotype was ameliorated by antiferroptotic compounds, iron chelators and HO-1 inhibitors. During COPD, the accumulation of lipid peroxidation drives ferroptosis-sensitive M2-like AMs, while M1-like AMs show characteristics of ferroptosis resistance. Ferroptotic M2 AMs lose their anti-inflammatory and repair functions but provoke inflammatory responses, resulting in consistent inflammation and tissue damage in the presence of M1 AMs in COPD.ConclusionAppropriate interventions in ferroptosis can reduce the occurrence of infections and acute onset, and delay the COPD process.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets