Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course

Kamilah Castro, Achilles Ntranos, Mario Amatruda, Maria Petracca, Peter Kosa, Emily Y. Chen, Johannes Morstein, Dirk Trauner, Corey T. Watson, Michael A. Kiebish, Bibiana Bielekova, Matilde Inglese, Ilana Katz Sand, Patrizia Casaccia

Research output: Contribution to journalArticle

Abstract

Background: Multiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS. Methods: Fifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-naïve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS. Findings: Higher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS. Interpretation: High BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti-proliferative genes. Fund: This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StatePublished - Jan 1 2019

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Ceramides
DNA Methylation
Multiple Sclerosis
Body Mass Index
Genes
Cell culture
Brain
Monocytes
Plasmas
Cell proliferation
Infiltration
Cell Culture Techniques
Magnetic resonance imaging
Animals
Relapsing-Remitting Multiple Sclerosis
Blood
Financial Management
Genetic Predisposition to Disease
Therapeutics
Animal Models

Keywords

  • Epigenetics
  • Immunity
  • Lipids
  • Neurodegeneration
  • Obesity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Castro, K., Ntranos, A., Amatruda, M., Petracca, M., Kosa, P., Chen, E. Y., ... Casaccia, P. (2019). Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course. EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.03.087

Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course. / Castro, Kamilah; Ntranos, Achilles; Amatruda, Mario; Petracca, Maria; Kosa, Peter; Chen, Emily Y.; Morstein, Johannes; Trauner, Dirk; Watson, Corey T.; Kiebish, Michael A.; Bielekova, Bibiana; Inglese, Matilde; Katz Sand, Ilana; Casaccia, Patrizia.

In: EBioMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Castro, K, Ntranos, A, Amatruda, M, Petracca, M, Kosa, P, Chen, EY, Morstein, J, Trauner, D, Watson, CT, Kiebish, MA, Bielekova, B, Inglese, M, Katz Sand, I & Casaccia, P 2019, 'Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course', EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.03.087
Castro, Kamilah ; Ntranos, Achilles ; Amatruda, Mario ; Petracca, Maria ; Kosa, Peter ; Chen, Emily Y. ; Morstein, Johannes ; Trauner, Dirk ; Watson, Corey T. ; Kiebish, Michael A. ; Bielekova, Bibiana ; Inglese, Matilde ; Katz Sand, Ilana ; Casaccia, Patrizia. / Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course. In: EBioMedicine. 2019.
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abstract = "Background: Multiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS. Methods: Fifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-na{\"i}ve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS. Findings: Higher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS. Interpretation: High BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti-proliferative genes. Fund: This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.",
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AU - Castro, Kamilah

AU - Ntranos, Achilles

AU - Amatruda, Mario

AU - Petracca, Maria

AU - Kosa, Peter

AU - Chen, Emily Y.

AU - Morstein, Johannes

AU - Trauner, Dirk

AU - Watson, Corey T.

AU - Kiebish, Michael A.

AU - Bielekova, Bibiana

AU - Inglese, Matilde

AU - Katz Sand, Ilana

AU - Casaccia, Patrizia

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N2 - Background: Multiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS. Methods: Fifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-naïve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS. Findings: Higher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS. Interpretation: High BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti-proliferative genes. Fund: This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.

AB - Background: Multiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS. Methods: Fifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-naïve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS. Findings: Higher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS. Interpretation: High BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti-proliferative genes. Fund: This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.

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KW - Lipids

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KW - Obesity

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