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 TrotteinDavid 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, Raphaël Rodriguez

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)386-394
Number of pages9
Issue number7960
Early online date26 Apr 2023
Publication statusPublished - 11 May 2023
Externally publishedYes

ASJC Scopus subject areas

  • General


Dive into the research topics of 'A druggable copper-signalling pathway that drives inflammation'. Together they form a unique fingerprint.

Cite this