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 branchedchain 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

Wildtype motoneurons, ALS‐Linked SOD1 mutation and glutamate profoundly modify astrocyte metabolism and lactate shuttling

“…These observations are consistent with our findings, that is, identification of a perturbation of lactate metabolism from experiments obtained from spinal cord of SOD1 G93A mice. We previously observed no change in lactate level in the cortex of SOD1 G93A mice [results from previous study done by our team (Patin et al, )]. Importantly, as study design, disease evolution, brain regions and timing of sample collection were different, we consider that findings about the sense of metabolites levels changes are not comparable and cannot be interpreted.…”

“…We then aimed to compare these findings on astrocytes and extra‐cellular metabolic ALS signature with findings obtained from the cortex of mouse model of ALS [data not shown from a previous study done by our team (Patin et al, )]. An OPLS‐DA model and univariate analysis performed on cortex metabolites obtained from symptomatic transgenic SOD1 G93A mice revealed common discriminating metabolites between this in vivo model and our in vitro models (Table ).…”

“… Discriminating metabolites found in cortex of SOD1 G93A mice relative to those of wildtype mice [data not shown from a previous study (Patin et al )]. ↑ and ↓ indicate higher and lower levels, respectively in cortex of SOD1 G93A mice relative to those of wildtype mice.…”

“…We have compared metabolites altered in this in vitro ALS model to those found in the ALS mouse model (Patin et al, ) and in ALS patients (Blasco et al, ; Wuolikainen et al, ) (Table 4). We observed that in ALS‐associated condition, astrocytes displayed a low level of glycerophosphocholine as found in SOD1 G93A transgenic mice and additionally showed a decreased level of docosahexaenoic acid (DHA) as previously reported in SOD1 G93A mice (Arima et al, ).…”

Potential neurotoxicity of prenatal exposure to sevoflurane on offspring: Metabolomics investigation on neurodevelopment and underlying mechanism

“…Arginine/proline metabolism is an important metabolic pathway associated with neurodegenerative diseases (Patin et al, 2016b), and arginine and proline have been proposed as potential biomarkers of Alzheimer's disease recently (Ibanez et al, 2012). In present study, pathway analysis suggested that arginine/proline metabolism was the most important metabolic pathway in this process; in addition, arginine/proline metabolism was abnormal inflammation models (Drago et al, 2016; Patin et al, 2016a), which might suggest that sevoflurane induced neuroinflammation followed by altered arginine/proline metabolism and led to neurological damage ultimately.…”