title: Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism.
abstract: In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic impairment and neuroinflammation. Playing an important role in the regulation of both phenomena, interleukin (IL)-6, a major cytokine of the inflammatory response has been proposed as a target for management of ALS. Although a pilot clinical trial provided promising results in humans, another recent preclinical study showed that knocking out the IL-6 gene in mice carrying ALS did not improve clinical outcome. In this study, we aimed to determine the relevance of the IL-6 pathway blockade in a mouse model of ALS by using a pharmacological antagonist of IL-6, a murine surrogate of tocilizumab, namely MR16-1. We analyzed the immunological and metabolic effects of IL-6 blockade by cytokine measurement, blood cell immunophenotyping, targeted metabolomics, and transcriptomics. A deleterious clinical effect of MR16-1 was revealed, with a speeding up of weight loss (p = 0.0041) and decreasing body weight (p < 0.05). A significant increase in regulatory T-cell count (p = 0.0268) and a decrease in C-X-C ligand-1 concentrations in plasma (p = 0.0479) were observed. Metabolomic and transcriptomic analyses revealed that MR16-1 mainly affected branched-chain amino acid, lipid, arginine, and proline metabolism. IL-6 blockade negatively affected body weight, despite a moderated anti-inflammatory effect. Metabolic effects of IL-6 were mild compared with metabolic disturbances observed in ALS, but a modification of lipid metabolism by therapy was identified. These results indicate that IL-6 blockade did not improve clinical outcome of a mutant superoxide dismutase 1 mouse model of ALS.
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France. patin.franck@gmail.com.|CHRU de Tours, Laboratoire de Biochimie et de Biologie Moléculaire, Tours, France. patin.franck@gmail.com.
authors.forename: Franck
authors.initials: F
authors.lastname: Patin
authors.affiliation: INSERM, UMR 1100 "Centre d'étude des Pathologies Respiratoires, Université François Rabelais, Tours, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Baranek
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.|CHRU de Tours, Laboratoire de Biochimie et de Biologie Moléculaire, Tours, France.|PPF "Analyse des systèmes biologiques", Université François Rabelais de Tours, Tours, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vourc'h
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.|PPF "Analyse des systèmes biologiques", Université François Rabelais de Tours, Tours, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Nadal-Desbarats
authors.affiliation: Centre Universitaire de Mesures et d'Analyses (CUMA), Université de Lille 2, Lille, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Goossens
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Marouillat
authors.affiliation: CHU Lille, Centre de Biologie et de Pathologie, F-59000, Lille, France.
authors.forename: Anne-Frédérique
authors.initials: AF
authors.lastname: Dessein
authors.affiliation: Centre Universitaire de Mesures et d'Analyses (CUMA), Université de Lille 2, Lille, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Descat
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.
authors.forename: Blandine Madji
authors.initials: BM
authors.lastname: Hounoum
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.|CHRU de Tours, Laboratoire de Biochimie et de Biologie Moléculaire, Tours, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Bruno
authors.affiliation: CHRU de Tours, Laboratoire d'Immunologie, Tours, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Watier
authors.affiliation: INSERM, UMR 1100 "Centre d'étude des Pathologies Respiratoires, Université François Rabelais, Tours, France.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Si-Tahar
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leman
authors.affiliation: CHU de Poitiers, Laboratoire d'Immunologie, Poitiers, France.|Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, UPRES EA4331, Pôle Biologie Santé, Université de Poitiers, Poitiers, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lecron
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.|CHRU de Tours, Laboratoire de Biochimie et de Biologie Moléculaire, Tours, France.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Andres
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.|CHRU de Tours, Fédération des CRCSLA Tours-Limoges (LITORALS), Tours, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Corcia
authors.affiliation: INSERM, UMR U930 "Imagerie et Cerveau", Université François Rabelais, Tours, France.|CHRU de Tours, Laboratoire de Biochimie et de Biologie Moléculaire, Tours, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blasco
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use*; D001835:Body Weight / Q000235:genetics; D016207:Cytokines / Q000097:blood; D004185:Disability Evaluation; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D053263:Gene Regulatory Networks; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D007155:Immunologic Factors; D015850:Interleukin-6; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; C502936:tocilizumab
keywords: Amyotrophic lateral sclerosis; MR16-1; metabolism; metabolomics; transcriptomics,interleukin-6