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.2014 May;124(5):2188-92.
doi: 10.1172/JCI72151. Epub 2014 Apr 1.

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

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

Hui Chen et al. J Clin Invest.2014 May.

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.

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Figures

Figure 1
Figure 1. DMF treatment attenuates the severity of EAE in wild-type mice but not inHca2–/– mice.
(A) EAE clinical scores for wild-type andHca2–/– mice (n = 10–15 per group) that were treated orally with vehicle or DMF (30 mg/kg body weight, twice per day). The transient partial remission observed in this experiment in theHca2–/– groups was not reproduced in other experiments and therefore is not a general feature ofHca2–/– mice (see Supplemental Figure 1, A and B). **P < 0.01 for comparison between “WT + Vehicle” and “WT + DMF” by nonparametric Mann-Whitney test. (B–D) DMF reduced the area under the curve (AUC), the peak score, and the day of disease onset in wild-type mice but not inHca2–/– mice.P = 0.0001, Kruskal-Wallis for AUC;P = 0.0003, Kruskal-Wallis test for peak scores;P = 0.0002, Kruskal-Wallis test for day of onset. ***P < 0.001 (Dunn’s multiple comparison test). NS, nonsignificant. (E andF) Immune cell infiltration was assessed by H&E staining of spinal cord sections on dpi 28 (n = 6–7).P = 0.0002 (2-way ANOVA for drug treatment); ***P < 0.001 (Bonferroni post-hoc test). Scale bar: 100 μm. (G andH) White matter demyelination was determined by Luxol Fast Blue staining of spinal cord sections on dpi 28 (n = 6–7).P < 0.0125 (2-way ANOVA for drug treatment); **P < 0.01 (Bonferroni post-hoc test). Scale bar: 100 μm. (E–H) Clinical scores of mice are given in Supplemental Figure 1A. Data represent mean ± SEM.
Figure 2
Figure 2. DMF treatment reduces neutrophil infiltration into the spinal cords in wild-type mice but not inHca2–/– mice with EAE.
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’st test with Bonferroni correction).
Figure 3
Figure 3. MMF inhibits neutrophil adhesion and migration via HCA2.
(A–F) Neutrophils expressed HCA2. Purified (A–C) peritoneal neutrophils and (D–F) spinal cord sections fromHca2mRFP 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 andD) 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 ofHca2–/– 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 inHca2–/– 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).
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