Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2
Monomethyl fumarate (MMF) and its prodrug dimethyl fumarate (DMF) are currently the most widely used agents for the treatment of multiple sclerosis (MS). However, not all patients benefit from DMF. We hypothesized that the variable response of patients may be due to their diet. In support of this hypothesis, mice subjected to experimental autoimmune encephalomyelitis (EAE), a model of MS, did not benefit from DMF treatment when fed a lauric acid (LA)-rich diet. Mice on normal chow (NC) diet, in contrast, and even more so mice on high-fiber (HFb) diet showed the expected protective DMF effect. DMF lacked efficacy in the LA diet-fed group despite similar resorption and preserved effects on plasma lipids. When mice were fed the permissive HFb diet, the protective effect of DMF treatment depended on hydroxycarboxylic receptor 2 (HCAR2), which is highly expressed in neutrophil granulocytes. Indeed, deletion of <i>Hcar2</i> in neutrophils abrogated DMF protective effects in EAE. Diet had a profound effect on the transcriptional profile of neutrophils and modulated their response to MMF. In summary, DMF required HCAR2 on neutrophils as well as permissive dietary effects for its therapeutic action. Translating the dietary intervention into the clinic may improve MS therapy.
Authors
- Joanna Kosinska (ORCID: https://orcid.org/0000-0003-3025-3685)
- Jöerg Heeren (ORCID: https://orcid.org/0000-0002-5647-1034)
- Markus Schwaninger (ORCID: https://orcid.org/0000-0002-4510-9718)
- Helge Müller‐Fielitz (ORCID: https://orcid.org/0000-0003-2815-4426)
- Matthias Gunzer (ORCID: https://orcid.org/0000-0002-5534-6055)
- Rubén Nogueiras (ORCID: https://orcid.org/0000-0002-9976-9930)
- Misa Hirose (ORCID: https://orcid.org/0000-0002-8909-4693)
- Nina Wettschureck (ORCID: https://orcid.org/0000-0001-6858-1460)
- Malte Spielmann (ORCID: https://orcid.org/0000-0002-0583-4683)
- Kristian Händler (ORCID: https://orcid.org/0000-0001-5273-5277)
- Sven Geisler (ORCID: https://orcid.org/0000-0002-5128-4467)
- Axel Künstner (ORCID: https://orcid.org/0000-0003-0692-2105)
- Anna Worthmann (ORCID: https://orcid.org/0000-0002-4731-3974)
- Julian C. Assmann (ORCID: https://orcid.org/0000-0002-3750-7126)
- Vincent Prévot (ORCID: https://orcid.org/0000-0001-7185-3615)
- Hauke Busch (ORCID: https://orcid.org/0000-0003-4763-4521)
- Christian D. Sadik (ORCID: https://orcid.org/0000-0001-6701-048X)
- Julica Inderhees (ORCID: https://orcid.org/0000-0003-4523-3652)
- Stefan Offermanns (ORCID: https://orcid.org/0000-0001-8676-6805)
Institutions
- Inserm (FR)
- Universität Hamburg (DE)
- Universidade de Santiago de Compostela (ES)
- Université de Lille (FR)
- Max Planck Institute for Heart and Lung Research (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- University Hospital Schleswig-Holstein (DE)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Institute of Pharmacology (CZ)
- Lille Neurosciences & Cognition (FR)
- University of Duisburg-Essen (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- eLife
- Published
- 2025-04-23
- DOI
- https://doi.org/10.7554/elife.98970
- Citations
- 3
- Primary Topic
- Ginger and Zingiberaceae research
- Type
- article
- Field-Weighted Citation Impact
- 4.67
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung