Journal Article

A druggable copper-signalling pathway that drives inflammation

Solier, Stéphanie, Müller, Sebastian, Emam, Laila, Gestraud, Pierre, Gaillet, Christine, Sencio, Valentin, Dingli, Florent, Cañeque, Tatiana, Versini, Antoine, Manel, Nicolas, Bègue, Anne-Laure, Annane, Djillali, Näser, Emmanuelle, Robil, Cyril, Sindikubwabo, Fabien, Loew, Damarys, Puisieux, Alain, Kroemer, Guido, Watson, Sarah, Pantoș, G. Dan, Meunier, Etienne, Cougoule, Céline, Salmon, Hélène, Baron, Leeroy, Mansart, Arnaud, Dawson, Mark A., Servant, Nicolas, Rodriguez, Raphaël, Péricat, David, Gandon, Vincent, Durand, Sylvère, Wu, Ting-Di, Baulande, Sylvain, Trottein, François

2023

Overview

Inflammation is a complex physiological process triggered in response to harmful stimuli 1 . 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 diseases 2 – 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. Cellular uptake of copper( ii ) by CD44 has a key role in regulating cellular plasticity via copper( ii )-dependent downstream signalling events.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/109 / 13/89 / 14/1 / 14/63 / 38/15 / 38/90 / 38/91 / 631/154 / 631/250/256 / 631/337/176 / 631/80/86 / 631/92/321 / 64/60 / 82/58 / 96/31 / Animal models / Animals / Biology / Cancer / CD44 antigen / Cell activation / Cell Plasticity - drug effects / Cell Plasticity - genetics / Cell surface / Copper / Copper - metabolism / Cytochrome / Epigenesis, Genetic - drug effects / Epigenetics / Glycoproteins / Heavy metals / Humanities and Social Sciences / Hydrogen peroxide / Hydrogen Peroxide - metabolism / Immune system / Inflammation / Inflammation - drug therapy / Inflammation - genetics / Inflammation - immunology / Inflammation - metabolism / Inflammation - pathology / Labeling / Life Sciences / Macrophage Activation - drug effects / Macrophage Activation - genetics / Macrophages / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Macrophages - pathology / Mass spectrometry / Metabolism / Metals / Metformin / Metformin - analogs & derivatives / Mice / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / multidisciplinary / NAD / NAD - metabolism / Oxidation-Reduction / Phenotypes / Physiology / Plastic properties / Plasticity / Redox properties / Science / Science (multidisciplinary) / Scientific imaging / Signal transduction / Signal Transduction - drug effects