Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR
- University of Lübeck, Germany
- University Medical Center Hamburg-Eppendorf, Germany
- University of Duisburg-Essen, Germany
- Univ. Lille, Inserm, France
- University of Santiago de Compostela, Spain
- Max Planck Institute for Heart and Lung Research, Germany
Abstract
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-rich (LA) 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 Hcar2 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.
Data availability
Raw RNA sequencing data have been deposited in Gene Expression Omnibus under accession number GSE263752. Lipidomics and metabolomics data are available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org where it has been assigned Project ID (PR001962). The data can be accessed directly via http://dx.doi.org/10.21228/M83X6D. This repository is supported by Metabolomics Workbench/National Metabolomics Data Repository (NMDR) (grant# U2C-DK119886), Common Fund Data Ecosystem (CFDE) (grant# 3OT2OD030544) and Metabolomics Consortium Coordinating Center (M3C) (grant# 1U2C-DK119889). All raw data included in the main figures and the supplementary information are fully available upon request.
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Diet modulates the protective effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCA2NIH Common Fund's National Metabolomics Data Repository.
Article and author information
Author details
Markus Schwaninger
Funding
European Research Council (810331)
- Vincent Prévot
- Ruben Nogueiras
- Markus Schwaninger
Deutsche Forschungsgemeinschaft (SCHW 416/12-1)
- Markus Schwaninger
Deutsche Forschungsgemeinschaft (WE 2891/2-1)
- Nina Wettschureck
Bundesministerium für Bildung und Forschung (Outlive-CRC-01KD2103A)
- Axel Künstner
- Hauke Busch
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Experimental procedures were approved by the local animal ethics committee (Ministerium für Landwirtschaft, ländliche Räume, Europa und Verbraucherschutz, Kiel, Germany, 106-8-17, 50-6-20, 28-4-22).
Copyright
© 2025, Kosinska et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR
eLife 14:e98970.
https://doi.org/10.7554/eLife.98970
