Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2

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 hy...

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Main Authors: Joanna Kosinska, Julian C Assmann, Julica Inderhees, Helge Müller-Fielitz, Kristian Händler, Sven Geisler, Axel Künstner, Hauke Busch, Anna Worthmann, Joerg Heeren, Christian D Sadik, Matthias Gunzer, Vincent Prévot, Ruben Nogueiras, Misa Hirose, Malte Spielmann, Stefan Offermanns, Nina Wettschureck, Markus Schwaninger
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2025-04-01
Series:eLife
Subjects:
multiple sclerosis
neutrophils
experimental autoimmune encephalomyelitis
Online Access:https://elifesciences.org/articles/98970
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Summary: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 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.
ISSN:2050-084X

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