Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis

Aiden Haghikia, Simon Faissner, Derek Pappas, Bartosz Pula, Denis A. Akkad, Larissa Arning, Sabrina Ruhrmann, Alexander Duscha, Ralf Gold, Sergio E. Baranzini, Sunny Malhotra, Xavier Montalban, Manuel Comabella, Andrew Chan

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Abstract

© 2014 The Author(s). Background: Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism. Objective: The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+ T cells. Methods: Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+ cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (m) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+ cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed. Results: IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+ T cells compared to controls (p < 0.001). Mitochondrial effects were reflected by depolarization of m. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders (p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels. Conclusion: Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+ T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.
Original languageEnglish
Pages (from-to)1262-1270
JournalMultiple Sclerosis
Volume21
Issue number10
DOIs
Publication statusPublished - 8 Sep 2015

Keywords

  • disease-modifying therapy (DMT)
  • immune cellular energy metabolism
  • interferon-β
  • Multiple sclerosis
  • oxidative phosphorylation
  • PGC-1α

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    Haghikia, A., Faissner, S., Pappas, D., Pula, B., Akkad, D. A., Arning, L., Ruhrmann, S., Duscha, A., Gold, R., Baranzini, S. E., Malhotra, S., Montalban, X., Comabella, M., & Chan, A. (2015). Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis. Multiple Sclerosis, 21(10), 1262-1270. https://doi.org/10.1177/1352458514561909