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

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 hydroxyearboxylic acid receptor 2 (HCA(2)), a G protein-coupled membrane receptor. Here, we evaluated the contribution of HCA(2) 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 HCA(2) is required for the therapeutic effect of DMF. In particular, DMF decreased the number of infiltrating neutrophils in a HCA(2)-dependent manner, likely by interfering with neutrophil adhesion to endothelial cells and chemotaxis. Together, our data indicate that HCA(2) mediates the therapeutic effects of DMF in EAE. Furthermore, identification of HCA(2) as a molecular target may help to optimize MS therapy.