A druggable copper-signalling pathway that drives inflammation

Stéphanie Solier, Sebastian Müller, Tatiana Cañeque, Antoine Versini, Arnaud Mansart, Fabien Sindikubwabo, Leeroy Baron, Laila Emam, Pierre Gestraud, G. Dan Pantoș, Vincent Gandon, Christine Gaillet, Ting-Di Wu, Florent Dingli, Damarys Loew, Sylvain Baulande, Sylvère Durand, Valentin Sencio, Cyril Robil, François Trottein, David Péricat, Emmanuelle Näser, Céline Cougoule, Etienne Meunier, Anne-Laure Bègue, Hélène Salmon, Nicolas Manel, Alain Puisieux, Sarah Watson, Mark A. Dawson, Nicolas Servant, Guido Kroemer, Djillali Annane and Raphaël Rodriguez ()
Additional contact information
Stéphanie Solier: PSL Research University
Sebastian Müller: PSL Research University
Tatiana Cañeque: PSL Research University
Antoine Versini: PSL Research University
Arnaud Mansart: Paris Saclay University, UVSQ, INSERM, 2I
Fabien Sindikubwabo: PSL Research University
Leeroy Baron: PSL Research University
Laila Emam: Paris Saclay University, UVSQ, INSERM, 2I
Pierre Gestraud: CBIO-Centre for Computational Biology, Institut Curie, INSERM, Mines ParisTech
G. Dan Pantoș: University of Bath
Vincent Gandon: CNRS, Paris Saclay University
Christine Gaillet: PSL Research University
Ting-Di Wu: PSL Research University
Florent Dingli: PSL Research University
Damarys Loew: PSL Research University
Sylvain Baulande: PSL Research University
Sylvère Durand: Institut Gustave Roussy
Valentin Sencio: Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, CIIL
Cyril Robil: Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, CIIL
François Trottein: Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, CIIL
David Péricat: University of Toulouse, CNRS
Emmanuelle Näser: University of Toulouse, CNRS
Céline Cougoule: University of Toulouse, CNRS
Etienne Meunier: University of Toulouse, CNRS
Anne-Laure Bègue: Institut Curie, INSERM, PSL Research University
Hélène Salmon: Institut Curie, INSERM, PSL Research University
Nicolas Manel: Institut Curie, INSERM, PSL Research University
Alain Puisieux: PSL Research University
Sarah Watson: PSL Research University
Mark A. Dawson: Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology
Nicolas Servant: CBIO-Centre for Computational Biology, Institut Curie, INSERM, Mines ParisTech
Guido Kroemer: Institut Gustave Roussy
Djillali Annane: Paris Saclay University, UVSQ, INSERM, 2I
Raphaël Rodriguez: PSL Research University

Nature, 2023, vol. 617, issue 7960, 386-394

Abstract: Abstract Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2–4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(ii) in mitochondria of inflammatory macrophages that catalyses 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 supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

Date: 2023
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DOI: 10.1038/s41586-023-06017-4

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