Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE
Hui Chen, … , Nina Wettschureck, Markus Schwaninger
Hui Chen, … , Nina Wettschureck, Markus Schwaninger
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):2188-2192. https://doi.org/10.1172/JCI72151.
View: Text | PDF
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

×

Figure 3

MMF inhibits neutrophil adhesion and migration via HCA2.

Options: View larger image (or click on image) Download as PowerPoint
MMF inhibits neutrophil adhesion and migration via HCA2. (A–F) Neutrop...
(A–F) Neutrophils expressed HCA2. Purified (A–C) peritoneal neutrophils and (D–F) spinal cord sections from Hca2mRFP reporter mice subjected to EAE were stained with (B) anti–Ly-6G and (E) anti-PMN (Ly-6G/Ly-6C) antibodies specific for neutrophils (green). (A and D) mRFP signal (red) represents HCA2 expression. Arrows indicate neutrophils stained by anti-PMN and expressing HCA2. Asterisks indicate mRFP+ and anti-PMN– cells most likely representing macrophages or microglia. Scale bar: 40 μm. (G) MMF (100 μM) reduced the adhesion of wild-type neutrophils but not of Hca2–/– neutrophils to TNF-stimulated bEnd.3 cells. Values are mean ± SEM (n = 4) in 1 of 2 experiments with similar results. P < 0.05 (2-way ANOVA for drug treatment); *P < 0.05 (Bonferroni post-hoc test). (H) MMF inhibited the CXCL2-induced migration in wild-type neutrophils but not in Hca2–/– neutrophils. Values are mean ± SEM (n = 3–4) in 1 of 3 experiments with similar results. P = 0.05 (2-way ANOVA for drug treatment); *P < 0.05 (Bonferroni post-hoc test).