title: 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.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Julian C
authors.initials: JC
authors.lastname: Assmann
authors.forename: Antje
authors.initials: A
authors.lastname: Krenz
authors.forename: Mahbubur
authors.initials: M
authors.lastname: Rahman
authors.forename: Myriam
authors.initials: M
authors.lastname: Grimm
authors.forename: Christian M
authors.initials: CM
authors.lastname: Karsten
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Nina
authors.initials: N
authors.lastname: Wettschureck
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D000069462:Dimethyl Fumarate; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D005650:Fumarates; C473652:Hcar2 protein, mouse; D007166:Immunosuppressive Agents; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D000069462:Dimethyl Fumarate