title: Repulsive guidance molecule-a is involved in Th17-cell-induced neurodegeneration in autoimmune encephalomyelitis.
abstract: Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation, demyelination, and neurodegeneration in the CNS. Although it is important to prevent neurodegeneration for alleviating neurological disability, the molecular mechanism of neurodegeneration remains largely unknown. Here, we report that repulsive guidance molecule-a (RGMa), known to regulate axonal growth, is associated with neurodegeneration in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. RGMa is highly expressed in interleukin-17-producing CD4(+) T cells (Th17 cells). We induced EAE by adoptive transfer of myelin oligodendrocyte glycoprotein (MOG)-specific Th17 cells and then inhibited RGMa with a neutralizing antibody. Inhibition of RGMa improves EAE scores and reduces neuronal degeneration without altering immune or glial responses. Th17 cells induce cultured cortical neuron death through RGMa-neogenin and Akt dephosphorylation. Our results demonstrate that RGMa is involved in Th17-cell-mediated neurodegeneration and that RGMa-specific antibody may have a therapeutic effect in MS.
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Tanabe
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan. Electronic address: yamashita@molneu.med.osaka-u.ac.jp.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D001369:Axons / Q000473:pathology; D002448:Cell Adhesion; D016923:Cell Death; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007109:Immunity; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; C483496:Rgma protein, mouse; D051057:Proto-Oncogene Proteins c-akt