Combined Metabolomics and Transcriptomics ...
Document type :
Article dans une revue scientifique
PMID :
Permalink :
Title :
Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism
Author(s) :
Patin, Franck [Auteur]
Baranek, Thomas [Auteur]
Vourc'h, Patrick [Auteur]
Nadal-Desbarats, Lydie [Auteur]
Goossens, Jean-Francois [Auteur]
Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA]
Marouillat, Sylviane [Auteur]
Dessein, Anne-Frederique [Auteur]
Descat, Amandine [Auteur]
Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA]
Hounoum Blandine, Madji [Auteur]
Bruno, Clement [Auteur]
Watier, Herve [Auteur]
Si-Tahar, Mustafa [Auteur]
Leman, Samuel [Auteur]
Lecron, Jean-Claude [Auteur]
Andres Christian, R [Auteur]
Corcia, Philippe [Auteur]
Blasco, Helene [Auteur]
Baranek, Thomas [Auteur]
Vourc'h, Patrick [Auteur]
Nadal-Desbarats, Lydie [Auteur]
Goossens, Jean-Francois [Auteur]

Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA]
Marouillat, Sylviane [Auteur]
Dessein, Anne-Frederique [Auteur]
Descat, Amandine [Auteur]
Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA]
Hounoum Blandine, Madji [Auteur]
Bruno, Clement [Auteur]
Watier, Herve [Auteur]
Si-Tahar, Mustafa [Auteur]
Leman, Samuel [Auteur]
Lecron, Jean-Claude [Auteur]
Andres Christian, R [Auteur]
Corcia, Philippe [Auteur]
Blasco, Helene [Auteur]
Journal title :
Neurotherapeutics
Abbreviated title :
Neurotherapeutics
Volume number :
13
Pages :
905-917
Publication date :
2016
HAL domain(s) :
Sciences du Vivant [q-bio]
French 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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
CHU Lille
CHU Lille
Collections :
Research team(s) :
Modélisation biopharmaceutique et pharmacocinétique
Submission date :
2019-02-26T17:11:44Z
2021-06-04T07:46:54Z
2021-06-04T07:46:54Z