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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.

SUBMITTER: Patin F

PROVIDER: S-EPMC5081117 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism.

Patin Franck F Baranek Thomas T Vourc'h Patrick P Nadal-Desbarats Lydie L Goossens Jean-François JF Marouillat Sylviane S Dessein Anne-Frédérique AF Descat Amandine A Hounoum Blandine Madji BM Bruno Clément C Watier Hervé H Si-Tahar Mustafa M Leman Samuel S Lecron Jean-Claude JC Andres Christian R CR Corcia Philippe P Blasco Hélène H

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20161001 4

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 i ...[more]

PMID: 27444617

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Project description:Brazil and many other Latin American countries are areas of endemicity for different neglected diseases, and the fungal infection paracoccidioidomycosis (PCM) is one of them. Among the clinical manifestations, pneumopathy associated with skin and mucosal lesions is the most frequent. PCM definitive diagnosis depends on yeast microscopic visualization and immunological tests, but both present ambiguous results and difficulty in differentiating PCM from other fungal infections. This research has employed metabolomics analysis through high-resolution mass spectrometry to identify PCM biomarkers in serum samples in order to improve diagnosis for this debilitating disease. To upgrade the biomarker selection, machine learning approaches, using Random Forest classifiers, were combined with metabolomics data analysis. The proposed combination of these two analytical methods resulted in the identification of a set of 19 PCM biomarkers that show accuracy of 97.1%, specificity of 100%, and sensitivity of 94.1%. The obtained results are promising and present great potential to improve PCM definitive diagnosis and adequate pharmacological treatment, reducing the incidence of PCM sequelae and resulting in a better quality of life.IMPORTANCE Paracoccidioidomycosis (PCM) is a fungal infection typically found in Latin American countries, especially in Brazil. The identification of this disease is based on techniques that may fail sometimes. Intending to improve PCM detection in patient samples, this study used the combination of two of the newest technologies, artificial intelligence and metabolomics. This combination allowed PCM detection, independently of disease form, through identification of a set of molecules present in patients' blood. The great difference in this research was the ability to detect disease with better confidence than the routine methods employed today. Another important point is that among the molecules, it was possible to identify some indicators of contamination and other infection that might worsen patients' condition. Thus, the present work shows a great potential to improve PCM diagnosis and even disease management, considering the possibility to identify concomitant harmful factors.

Dataset Information

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism.

Publications

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism.

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