2. Academic Validation
  3. Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity

Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity

  • Brain. 2021 Nov 29;144(10):3126-3141. doi: 10.1093/brain/awab307.
Marie Liebmann 1,  Lisanne Korn 1,  Claudia Janoschka 1,  Stefanie Albrecht 2,  Sarah Lauks 1,  Alexander M Herrmann 3,  Andreas Schulte-Mecklenbeck 1,  Nicholas Schwab 1,  Tilman Schneider-Hohendorf 1,  Maria Eveslage 4,  Brigitte Wildemann 5,  Felix Luessi 6,  Stephan Schmidt 7,  Martin Diebold 8,  Stefan Bittner 6,  Catharina C Gross 1,  Stjepana Kovac 1,  Frauke Zipp 6,  Tobias Derfuss 8,  Tanja Kuhlmann 2,  Simone König 9,  Sven G Meuth 3,  Heinz Wiendl 1,  Luisa Klotz 1
Affiliations

Affiliations

  • 1 Department of Neurology with Institute of Translational Neurology, University Hospital of Münster, Münster 48149, Germany.
  • 2 Institute of Neuropathology, University Hospital Münster, Münster 48149, Germany.
  • 3 Department of Neurology, University Hospital Düsseldorf, Düsseldorf 40225, Germany.
  • 4 Institute of Biostatistics and Clinical Research, University of Münster, Münster 48149, Germany.
  • 5 Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg 69120, Germany.
  • 6 Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz 55131, Germany.
  • 7 Bonn Neurological Practice, Bonn 53111, Germany.
  • 8 Laboratory of Clinical Neuroimmunology, Neurologic Clinic and Policlinic, Departments of Biomedicine and Clinical Research, University Hospital Basel, and University of Basel, Basel 4031, Switzerland.
  • 9 Core Unit Proteomics, Interdisciplinary Clinical Research Center, University of Münster, Münster 48149, Germany.
PMID: 34849598 DOI: 10.1093/brain/awab307
Abstract

Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the Reactive Oxygen Species scavenger glutathione. This causes an increase in mitochondrial Reactive Oxygen Species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial Reactive Oxygen Species levels not only result in enhanced T-cell Apoptosis in vitro as well as in dimethyl fumarate-treated patients, but are key for the well-known immunomodulatory effects of dimethyl fumarate both in vitro and in an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis. Indeed, dimethyl fumarate immune-modulatory effects on T cells were completely abrogated by pharmacological interference of mitochondrial Reactive Oxygen Species production. These data shed new LIGHT on dimethyl fumarate as bona fide immune-metabolic drug that targets the intracellular stress response in activated T cells, thereby restricting mitochondrial function and energetic capacity, providing novel insight into the role of oxidative stress in modulating cellular immune responses and T cell-mediated autoimmunity.

Keywords

T-cell; antioxidative T-cell capacities; autoimmunity; dimethyl fumarate; multiple sclerosis; metabolism.

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