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Epigenomic and lipidomic changes in Multiple Sclerosis patients with high Body Mass Index enhance the neurotoxic function of monocytes

ABSTRACT: The growing obesity “epidemic” has shed light on its negative impact on overall health status, not only in relation to cardiovascular disorders and metabolic syndrome, but also in regard to its influence on a variety of other health conditions, including autoimmune diseases, such as Multiple Sclerosis (MS). High Body Mass index (BMI) is a risk factor for MS, however, it is not known whether and how it could impact disease course. Several studies, including those on the Dutch Famine, have highlighted the role of epigenetic modifications in mediating phenotypic changes in response to metabolic shifts, suggesting that epigenetic changes could be a potential mechanism for BMI-driven differences in disease course. Using the Illumina 450K array, we identified genome-wide differences in DNA methylation between blood monocytes from therapy-naïve RRMS patients with high BMI compared to low BMI. Differences were subtle, however, were heavily skewed in the positive direction in the high BMI group, indicative of overall DNA hypermethylation. Further curation of differentially methylated genes, using stringent criteria, revealed enrichment in anti-inflammatory functions among the top hypermethylated genes. Thus, epigenomic changes related to inflammatory processes of monocytes are detected in MS patients with high BMI compared to those with low BMI and could potentially impact disease course by modulating immune-driven neurotoxicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103929 | GEO | 2019/06/20

SECONDARY ACCESSION(S): PRJNA407633

REPOSITORIES: GEO

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Project description:This study explored how chronic stress influences the activity of signaling pathways that regulate inflammation in the human monocyte transcriptome. The sample consisted of 33 adults caring for a family member with glioblastoma, a terminal brain cancer, and 47 control subjects whose lives were free of major stressors. The subjects were assessed on four occasions across an eight-month period. Relative to controls, caregivers’ monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor in monocytes. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys anti-inflammatory signals to monocytes. These transcriptional disparities were not attributable to demographic or behavioral confounds. They also were not attributable to differences in diurnal cortisol output, or the abundance of glucocorticoid receptor expressed by monocytes. In ex vivo studies of monocytes stimulated with the bacterial product lipopolysaccharide, caregivers showed increased production of the pro-inflammatory cytokine interleukin-6, and were less sensitive to cortisol-mediated inhibition of this response. These findings suggest a scenario wherein chronic stressors engender functional changes that hamper monocytes’ capacity to transduce cortisol’s anti-inflammatory signals. These changes occur in parallel with, and perhaps enable, greater inflammatory signaling via nuclear-factor kappa B. The resulting inflammatory milieu could serve as a pathogenic mechanism through which chronic stressors like caregiving accentuate vulnerability to later health problems. series type: Risk prediction Individual differences in basal leukocyte gene expression profiles as a function of chronic caregiving stress Characteristics included in statistical analyses of gene expression data are provided in each sample records. Please note that educational attainment is scored as following; 0=less than high school, 1=high school diploma or equivalent, 2=associate's degree, 3=bachelor's degree, 4=masters degree, 5=doctoral degree

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Epigenomic and lipidomic changes in Multiple Sclerosis patients with high Body Mass Index enhance the neurotoxic function of monocytes

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