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

58 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)386-394
Number of pages9
JournalNature
Volume617
Issue number7960
Early online date26 Apr 2023
DOIs
Publication statusPublished - 11 May 2023

Bibliographical note

Funding Information:
R.R. thanks J.-M. Lehn, S. Schreiber and R. Vale. This work was supported by the CNRS, INSERM, PSL Research University, Paris Saclay University, Ecole Polytechnique, University of Bath, University of Lille and Institut Pasteur (Lille). R.R. was supported by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 647973), Foundation Charles Defforey-Institut de France, Region IdF for NMR infrastructure, Ligue Contre le Cancer and the Ladies of Pompadour. G.K. was supported by ANR Grant Wilsonmed and LabEx Immuno-Oncology (ANR-18-IDEX-0001). D.A. was supported by FHU Sepsis and Programme d’Investissements d’avenir ANR-18-RHUS-0004-RHU records. ICP-MS platform at Institut de Physique du Globe de Paris is supported by IPGP multidisciplinary programme PARI and Region IdF (SESAME grant agreement no. 12015908). This work was granted access to the HPC resources of CINES under the allocation 2020-A0070810977 made by GENCI, the Balena High Performance Computing (HPC) Service at the University of Bath, the PICT-IbiSA@BDD Imaging Facility of Institut Curie, member of the France-BioImaging national research infrastructure (ANR-10-INBS-04), the ICGex NGS platform of Institut Curie (ANR-10-INBS-09-08, INCa-DGOS-465, INCa-DGOS-Inserm_12554), GenoToul ANEXPLO Animal Level 3 and TRI Facilities of the IPBS (Investissement d’Avenir and Foundation Bettencourt), the mass spectrometry platform supported by Région Ile-de-France (N°EX061034) and ITMO Cancer of Aviesan and INCa on funds administered by INSERM (N°21CQ016-00), and the cytometry platform of Institut Curie. We thank P. Benaroch, J.-L. Guerquin-Kern, M. Plays, J. Sampaio Lopes, D. Guillemot, O. Delattre and O. Neyrolles for support.

Data availability:
RNA-seq and ChIP–seq data are available at the Gene Expression Omnibus with accession reference GSE160864. The mass spectrometry proteomics raw data have been deposited to the ProteomeXchange Consortium via the PRIDE80 partner repository with the dataset identifier PXD038612. The donor number corresponds to the order of blood collection. Source data are provided with this paper.

ASJC Scopus subject areas

  • General

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