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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2025-04-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/98970 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850256082355617792 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Joanna Kosinska |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-48eed44c67fe4eb1ba8ac52d2b1ebf3e |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-48eed44c67fe4eb1ba8ac52d2b1ebf3e2025-08-20T01:56:42ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011410.7554/eLife.98970Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2Joanna Kosinska0https://orcid.org/0000-0003-3025-3685Julian C Assmann1Julica Inderhees2https://orcid.org/0000-0003-4523-3652Helge Müller-Fielitz3https://orcid.org/0000-0003-2815-4426Kristian Händler4Sven Geisler5Axel Künstner6https://orcid.org/0000-0003-0692-2105Hauke Busch7Anna Worthmann8Joerg Heeren9https://orcid.org/0000-0002-5647-1034Christian D Sadik10Matthias Gunzer11https://orcid.org/0000-0002-5534-6055Vincent Prévot12Ruben Nogueiras13Misa Hirose14Malte Spielmann15https://orcid.org/0000-0002-0583-4683Stefan Offermanns16https://orcid.org/0000-0001-8676-6805Nina Wettschureck17Markus Schwaninger18https://orcid.org/0000-0002-4510-9718Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany; Bioanalytic Core Facility, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, GermanyInstitute of Human Genetics, Universitätsklinikum Schleswig-Holstein, University of Lübeck and University of Kiel, Lübeck, GermanyCell Analysis Core Facility, University of Lübeck, Lübeck, GermanyLübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, GermanyLübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, GermanyDepartment of Biochemistry and Molecular Cell Biology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Biochemistry and Molecular Cell Biology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Dermatology, Allergy, and Venereology, University of Lübeck, Lübeck, GermanyInstitute for Experimental Immunology and Imaging, University Hospital, University of Duisburg-Essen, Essen, Germany; Leibniz-Institute for Analytical Sciences-ISAS, Dortmund, GermanyUniv. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, Lille, FranceUniversidade de Santiago de Compostela-Instituto de Investigation Sanitaria, Santiago de Compostela, SpainLübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, GermanyInstitute of Human Genetics, Universitätsklinikum Schleswig-Holstein, University of Lübeck and University of Kiel, Lübeck, GermanyMax Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, GermanyMax Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, GermanyInstitute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, GermanyMonomethyl 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.https://elifesciences.org/articles/98970multiple sclerosisneutrophilsexperimental autoimmune encephalomyelitis |
| spellingShingle | 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 Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2 eLife multiple sclerosis neutrophils experimental autoimmune encephalomyelitis |
| title | Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2 |
| title_full | Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2 |
| title_fullStr | Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2 |
| title_full_unstemmed | Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2 |
| title_short | Diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor HCAR2 |
| title_sort | diet modulates the therapeutic effects of dimethyl fumarate mediated by the immunometabolic neutrophil receptor hcar2 |
| topic | multiple sclerosis neutrophils experimental autoimmune encephalomyelitis |
| url | https://elifesciences.org/articles/98970 |
| work_keys_str_mv | AT joannakosinska dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT juliancassmann dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT julicainderhees dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT helgemullerfielitz dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT kristianhandler dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT svengeisler dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT axelkunstner dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT haukebusch dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT annaworthmann dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT joergheeren dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT christiandsadik dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT matthiasgunzer dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT vincentprevot dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT rubennogueiras dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT misahirose dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT maltespielmann dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT stefanoffermanns dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT ninawettschureck dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 AT markusschwaninger dietmodulatesthetherapeuticeffectsofdimethylfumaratemediatedbytheimmunometabolicneutrophilreceptorhcar2 |