Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE
Hui Chen, Julian C. Assmann, Antje Krenz, Mahbubur Rahman, Myriam Grimm, Christian M. Karsten, Jörg Köhl, Stefan Offermanns, Nina Wettschureck, Markus Schwaninger
Hui Chen, Julian C. Assmann, Antje Krenz, Mahbubur Rahman, Myriam Grimm, Christian M. Karsten, Jörg Köhl, Stefan Offermanns, Nina Wettschureck, Markus Schwaninger
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Brief Report Immunology

Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE

Abstract

Taken orally, the drug dimethyl fumarate (DMF) has been shown to improve functional outcomes for patients with MS; however, it is unclear how DMF mediates a protective effect. DMF and, more so, its active metabolite, monomethyl fumarate, are known agonists of the hydroxycarboxylic acid receptor 2 (HCA2), a G protein–coupled membrane receptor. Here, we evaluated the contribution of HCA2 in mediating the protective effect afforded by DMF in EAE, a mouse model of MS. DMF treatment reduced neurological deficit, immune cell infiltration, and demyelination of the spinal cords in wild-type mice, but not in Hca2–/– mice, indicating that HCA2 is required for the therapeutic effect of DMF. In particular, DMF decreased the number of infiltrating neutrophils in a HCA2-dependent manner, likely by interfering with neutrophil adhesion to endothelial cells and chemotaxis. Together, our data indicate that HCA2 mediates the therapeutic effects of DMF in EAE. Furthermore, identification of HCA2 as a molecular target may help to optimize MS therapy.

Authors

Hui Chen, Julian C. Assmann, Antje Krenz, Mahbubur Rahman, Myriam Grimm, Christian M. Karsten, Jörg Köhl, Stefan Offermanns, Nina Wettschureck, Markus Schwaninger

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Figure 2

DMF treatment reduces neutrophil infiltration into the spinal cords in wild-type mice but not in Hca2–/– mice with EAE.

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DMF treatment reduces neutrophil infiltration into the spinal cords in w...
The number of (A) CD45+CD4+ T helper cells, (B) CD45+CD8+ T cytotoxic cells, (C) CD45+CD11b+ macrophages, (D) CD45+Ly-6G+ neutrophils, and (E) CD45+CD11c+ dendritic cells in the spinal cord was quantified by flow cytometry on dpi 17. DMF or vehicle were given orally (30 mg/kg body weight, twice per day) starting from dpi 3. Results are expressed relative to the vehicle group of the same genotype. Data are mean ± SEM from 14 to 15 mice per group. *P < 0.05 (Student’s t test with Bonferroni correction).