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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents



ID: 711917.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE
Authors:Chen, H.; Assmann, J. C.; Krenz, A.; Rahman, M.; Grimm, M.; Karsten, C. M.; Kohl, J.; Offermanns, S.; Wettschureck, N.; Schwaninger, M.
Date of Publication (YYYY-MM-DD):2014-05
Title of Journal:J Clin Invest
Volume:124
Issue / Number:5
Start Page:2188
End Page:2192
Audience:Not Specified
Abstract / Description: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 (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.
Free Keywords:Animals; Cell Adhesion/drug effects/genetics; *Encephalomyelitis, Autoimmune, Experimental/drug; therapy/genetics/metabolism/pathology; Female; Fumarates/*pharmacology; Humans; Immunosuppressive Agents/*pharmacology; Mice; Mice, Knockout; Multiple Sclerosis/drug therapy/genetics/metabolism/pathology; Neutrophil Infiltration/*drug effects; Neutrophils/*metabolism/pathology; Receptors, G-Protein-Coupled/genetics/*metabolism; Receptors, Nicotinic/genetics/*metabolism
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1558-8238 (Electronic) 0021-9738 (Linking) %R 10.1172/JCI72151
URL:http://www.ncbi.nlm.nih.gov/pubmed/24691444 %^ 143...
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