2. Academic Validation
  3. A druggable copper-signalling pathway that drives inflammation

A druggable copper-signalling pathway that drives inflammation

  • Nature. 2023 May;617(7960):386-394. doi: 10.1038/s41586-023-06017-4.
Stéphanie Solier # 1,  Sebastian Müller # 1,  Tatiana Cañeque # 1,  Antoine Versini # 1,  Arnaud Mansart 2,  Fabien Sindikubwabo 1,  Leeroy Baron 1,  Laila Emam 2,  Pierre Gestraud 3,  G Dan Pantoș 4,  Vincent Gandon 5 6,  Christine Gaillet 1,  Ting-Di Wu 7 8,  Florent Dingli 9,  Damarys Loew 9,  Sylvain Baulande 10,  Sylvère Durand 11,  Valentin Sencio 12,  Cyril Robil 12,  François Trottein 12,  David Péricat 13,  Emmanuelle Näser 13 14,  Céline Cougoule 13,  Etienne Meunier 13,  Anne-Laure Bègue 15,  Hélène Salmon 15,  Nicolas Manel 15,  Alain Puisieux 1,  Sarah Watson 16,  Mark A Dawson 17 18,  Nicolas Servant 3,  Guido Kroemer 11 19 20,  Djillali Annane 2 21,  Raphaël Rodriguez 22
Affiliations

Affiliations

  • 1 Equipe Labellisée Ligue Contre le Cancer, Institut Curie, CNRS, INSERM, PSL Research University, Paris, France.
  • 2 Paris Saclay University, UVSQ, INSERM, 2I, Montigny-le-Bretonneux, France.
  • 3 CBIO-Centre for Computational Biology, Institut Curie, INSERM, Mines ParisTech, Paris, France.
  • 4 Department of Chemistry, University of Bath, Bath, UK.
  • 5 Institut de Chimie Moléculaire et des Matériaux d'Orsay, CNRS, Paris Saclay University, Orsay, France.
  • 6 Laboratoire de Chimie Moléculaire, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, Palaiseau, France.
  • 7 Institut Curie, PSL Research University, Paris, France.
  • 8 Multimodal Imaging Center, Paris Saclay University, CNRS, INSERM, Orsay, France.
  • 9 CurieCoreTech Mass Spectrometry Proteomic, Institut Curie, PSL Research University, Paris, France.
  • 10 ICGex Next-Generation Sequencing Platform, Institut Curie, PSL Research University, Paris, France.
  • 11 Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
  • 12 Université de Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, CIIL, Lille, France.
  • 13 Institut of Pharmacology and Structural Biology, University of Toulouse, CNRS, Toulouse, France.
  • 14 Cytometry and Imaging Core facility, Institute of Pharmacology and Structural Biology, University of Toulouse, CNRS, Toulouse, France.
  • 15 Institut Curie, INSERM, PSL Research University, Paris, France.
  • 16 Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.
  • 17 Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, Melbourne, Victoria, Australia.
  • 18 Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
  • 19 Centre de Recherche des Cordeliers, University of Paris, Sorbonne University, INSERM, Institut Universitaire de France, Paris, France.
  • 20 Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  • 21 Department of Intensive Care, Hôpital Raymond Poincaré, AP-HP, Garches, France.
  • 22 Equipe Labellisée Ligue Contre le Cancer, Institut Curie, CNRS, INSERM, PSL Research University, Paris, France. raphael.rodriguez@curie.fr.
  • # Contributed equally.
PMID: 37100912 DOI: 10.1038/s41586-023-06017-4
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.

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