Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

  1. Stéphanie Solier
  2. Sebastian Müller
  3. Tatiana Cañeque
  4. Antoine Versini
  5. Leeroy Baron
  6. Pierre Gestraud
  7. Nicolas Servant
  8. Laila Emam
  9. Arnaud Mansart
  10. G. Dan Pantoș
  11. Vincent Gandon
  12. Valentin Sencio
  13. Cyril Robil
  14. François Trottein
  15. Anne-Laure Bègue
  16. Hélène Salmon
  17. Sylvère Durand
  18. Ting-Di Wu
  19. Nicolas Manel
  20. Alain Puisieux
  21. Mark A. Dawson
  22. Sarah Watson
  23. Guido Kroemer
  24. Djillali Annane
  25. Raphaël Rodriguez

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Abstract

Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying inflammatory responses are not fully understood. Here, we show that the cell surface marker CD44, which characterizes activated immune cells, acts as a metal transporter that promotes copper uptake. We identified a chemically reactive pool of copper(II) in mitochondria of inflammatory macrophages that catalyzes NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD + enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with a rationally-designed dimer of metformin triggers distinct metabolic and epigenetic states that oppose macrophage activation. This drug reduces inflammation in mouse models of bacterial and viral (SARS-CoV-2) infections, improves well-being and increases survival. Identifying mechanisms that regulate the plasticity of immune cells provides the means to develop next-generation medicine. Our work illuminates the central role of copper as a regulator of cell plasticity and unveils a new therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

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    SciScore for 10.1101/2022.03.29.486253: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: Thank you for sharing your code and data.

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    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2022.03.29.486253v1 on bioRxiv