title: Molecular responses of mouse macrophages to copper and copper oxide nanoparticles inferred from proteomic analyses.
abstract: The molecular responses of macrophages to copper-based nanoparticles have been investigated via a combination of proteomic and biochemical approaches, using the RAW264.7 cell line as a model. Both metallic copper and copper oxide nanoparticles have been tested, with copper ion and zirconium oxide nanoparticles used as controls. Proteomic analysis highlighted changes in proteins implicated in oxidative stress responses (superoxide dismutases and peroxiredoxins), glutathione biosynthesis, the actomyosin cytoskeleton, and mitochondrial proteins (especially oxidative phosphorylation complex subunits). Validation studies employing functional analyses showed that the increases in glutathione biosynthesis and in mitochondrial complexes observed in the proteomic screen were critical to cell survival upon stress with copper-based nanoparticles; pharmacological inhibition of these two pathways enhanced cell vulnerability to copper-based nanoparticles, but not to copper ions. Furthermore, functional analyses using primary macrophages derived from bone marrow showed a decrease in reduced glutathione levels, a decrease in the mitochondrial transmembrane potential, and inhibition of phagocytosis and of lipopolysaccharide-induced nitric oxide production. However, only a fraction of these effects could be obtained with copper ions. In conclusion, this study showed that macrophage functions are significantly altered by copper-based nanoparticles. Also highlighted are the cellular pathways modulated by cells for survival and the exemplified cross-toxicities that can occur between copper-based nanoparticles and pharmacological agents.
authors.affiliation: Pro-MD team, Laboratoire de Chimie et Biologie des Métaux, UMR CNRS-CEA-UJF, Université Joseph Fourier, Grenoble 38054, France;
authors.forename: Sarah
authors.initials: S
authors.lastname: Triboulet
authors.forename: Catherine
authors.initials: C
authors.lastname: Aude-Garcia
authors.forename: Marie
authors.initials: M
authors.lastname: Carrière
authors.forename: Hélène
authors.initials: H
authors.lastname: Diemer
authors.forename: Fabienne
authors.initials: F
authors.lastname: Proamer
authors.forename: Aurélie
authors.initials: A
authors.lastname: Habert
authors.forename: Mireille
authors.initials: M
authors.lastname: Chevallet
authors.forename: Véronique
authors.initials: V
authors.lastname: Collin-Faure
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Strub
authors.forename: Daniel
authors.initials: D
authors.lastname: Hanau
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.forename: Nathalie
authors.initials: N
authors.lastname: Herlin-Boime
authors.forename: Thierry
authors.initials: T
authors.lastname: Rabilloud
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003300:Copper / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000633:toxicity*; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D024101:Mitochondrial Proteins; D009569:Nitric Oxide; D003300:Copper; D005978:Glutathione; C000520:cuprous oxide