title: Alpha-methylacyl-CoA racemase deletion has mutually counteracting effects on T-cell responses, associated with unchanged course of EAE.
abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Altering the metabolism of immune cells is an attractive strategy to modify their activity during autoimmunity in MS. We investigated the effect of modulating fatty acid metabolism in an animal model of MS, EAE. Alpha-methylacyl-CoA racemase (AMACR) converts R-configuration branched fatty acids into the S-configuration, thereby preparing them for β-oxidation. We observed a significant, disease-dependent elevation of AMACR expression in monocytes and T cells from blood, draining lymph nodes and spleen of EAE mice during the preclinical phase. In vitro analysis revealed that the proliferation of T cells was inhibited in AMACR KO mice, but T-cell polarization was switched toward a pathogenic state involving the production of more IFN-γ and IL-17, but less IL-4. These opposing effects appeared to cancel out each other in vivo, because AMACR KO EAE mice showed a marginal increase in the severity of early clinical symptoms. AMACR was not regulated in the white blood cells of MS patients. Our data show that AMACR is regulated in immune cells during EAE, but it is not a suitable target for the treatment of MS due to its opposing effects.
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Tafferner
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Frankfurt/Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Barthelmes
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Frankfurt/Main, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Eberle
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulshöfer
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Henke
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
authors.forename: Natasja
authors.initials: N
authors.lastname: deBruin
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Frankfurt/Main, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Mayer
authors.affiliation: Department of Neurology, Goethe-University Frankfurt, Frankfurt/Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Frankfurt/Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnham
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital Frankfurt, Frankfurt/Main, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schiffmann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology* / Q000276:immunology*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000276:immunology*; D019998:Racemases and Epimerases / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
chemical_list: D005227:Fatty Acids; C508717:IL17A protein, human; C098680:Il17a protein, mouse; D020381:Interleukin-17; D015847:Interleukin-4; D007371:Interferon-gamma; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase
keywords: Alpha-methylacyl-CoA racemase (AMACR); Cytokines; EAE; Multiple sclerosis; T cells