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

Nature Chemical Biology volume 16, pages 278–290 (2020)Cite this article

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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.

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Fig. 1: Differential sensitivity of activated M1 and alternatively activated M2 macrophages and microglia to RSL3-induced ferroptosis.
Fig. 2: Sensitivity of activated (M1) macrophages and microglial cells to RSL3-induced ferroptosis depends on the levels of iNOS expression.
Fig. 3: NO• protects cells against RSL3-induced ferroptosis.
Fig. 4: NO• suppresses RSL3-induced accumulation of oxidatively modified PE species in alternatively activated (M2) RAW 264.7 macrophages.
Fig. 5: iNOS/NO•-driven mechanisms of ferroptosis regulation in vivo.
Fig. 6: NO•/O2 interactions with 15-LOX-2 and entry/exit pathways observed in MD simulations of 15-LOX-2 and the 15-LOX-2–PEBP1 complex.

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Data availability

The raw data are available at the following link https://data.mendeley.com/datasets/t4jyhhf3gw/draft?a=76c6ac56-4305-463e-bebc-b004c2000edb.

Code used for the analysis of the MD simulations of NO• interactions with 15-LOX has been made available in two formats: (1) Jupyter Notebook and (2) html (https://onedrive.live.com/?authkey=%21AFEVmP5sOP1km0s&id=4960CA1B5C7F3FD%219568&cid=04960CA1B5C7F3FD).

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Acknowledgements

This work was supported by NIH (HL114453-06, U19AI068021, CA165065-06, NS076511, NS061817, P41GM103712) and by Russian academic excellence project ‘5-100’.

Author information

Author notes

  1. These authors contributed equally: Alexandr A. Kapralov, Qin Yang, Haider H. Dar.

  2. Deceased: Detcho A. Stoyanovsky.

Authors and Affiliations

  1. Department of Environmental and Occupational Health and Center for Free Radical and Antioxidant Health University of Pittsburgh, Pittsburgh, PA, USA

    Alexandr A. Kapralov, Haider H. Dar, Yulia Y. Tyurina, Indira H. Shrivastava, Vladimir A. Tyurin, Hsiu-Chi Ting, Galina V. Shurin, Margarita A. Artyukhova, Liubov A. Ponomareva, Detcho A. Stoyanovsky, Hülya Bayır & Valerian E. Kagan

  2. Department of Critical Care Medicine, Safar Center for Resuscitation Research, Children’s Neuroscience Institute, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

    Qin Yang, Tamil S. Anthonymuthu, Yuan Gao & Hülya Bayır

  3. The Wistar Institute, Philadelphia, PA, USA

    Rina Kim & Dmitry I. Gabrilovich

  4. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Rina Kim

  5. Department of Cell Biology, Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

    Claudette M. St. Croix

  6. Department of Computational and Systems Biology, Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

    Karolina Mikulska-Ruminska, Bing Liu, Indira H. Shrivastava & Ivet Bahar

  7. Institute of Physics, Faculty of Physics Astronomy and Informatics, Nicolaus Copernicus University in Toruń, Toruń, Poland

    Karolina Mikulska-Ruminska

  8. Department of Developmental Biology, Rangos Research Center of Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

    Yijen L. Wu

  9. Laboratory of Navigational Redox Lipidomics, Institute for Regenerative Medicine, IM Sechenov Moscow State Medical University, Moscow, Russia

    Margarita A. Artyukhova, Liubov A. Ponomareva, Peter S. Timashev & Valerian E. Kagan

  10. Mass Spectrometry Center, QOPNA, University of Aveiro, Aveiro, Portugal

    Rosario M. Domingues

  11. Department of Chemistry and CESAM&ECOMARE, University of Aveiro, Aveiro, Portugal

    Rosario M. Domingues

  12. Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA

    Joel S. Greenberger & Valerian E. Kagan

  13. Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    Rama K. Mallampalli

  14. Department of Chemistry, Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

    Valerian E. Kagan

  15. Department of Pharmacology and Chemical Biology, Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

    Valerian E. Kagan

Authors
  1. Alexandr A. Kapralov
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  2. Qin Yang
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  3. Haider H. Dar
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  4. Yulia Y. Tyurina
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  5. Tamil S. Anthonymuthu
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  6. Rina Kim
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Contributions

V.E.K. and H.B. conceived the study. A.A.K., Q.Y., H.H.D., G.V.S., H.-C.T., M.A.A. and L.A.P. performed experiments with cells. V.E.K., H.B. and D.I.G. designed in vivo experiments. Q.Y., Y.L.W., R.K. and Y.G. performed in vivo experiments. A.A.K., Q.Y. and H.H.D. analyzed the data. Y.Y.T., T.S.A. and V.A.T. performed MS measurements and analyzed data. Y.Y.T., T.S.A. and R.M.D. discussed and interpreted MS results. K.M.-R., B.L. and I.H.S. performed computational modelling. I.B. supervised computational studies. C.M.S.C. performed imaging experiments and participated in interpreting them. H.B., D.A.S., R.K.M. and D.I.G. participated in formulating the idea and interpreting the data. P.S.T. and J.S.G. participated in the discussion and helped in writing the manuscript. Y.Y.T., I.B. and H.B. participated in writing the manuscript. H.B. and V.E.K. wrote the manuscript.

Corresponding authors

Correspondence to Dmitry I. Gabrilovich, Hülya Bayır or Valerian E. Kagan.

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Supplementary Information

Supplementary Figs. 1–11.

Reporting Summary

Supplementary Tables 1 and 2

Supplementary Tables 1 and 2.

Supplementary Video 1

Fragment of MD simulations of competitive binding of NO and O2 molecules to 15-LOX-2.

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Kapralov, A.A., Yang, Q., Dar, H.H. et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol 16, 278–290 (2020). https://doi.org/10.1038/s41589-019-0462-8

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