title: A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.
abstract: Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target.
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Arima
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Atsumi
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Dentistry, Tsurumi University, Yokohama, Japan.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishikawa
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stofkova
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Takuto
authors.initials: T
authors.lastname: Ohki
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Higuchi
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Morimoto
authors.affiliation: Institute of Neuropathology, Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wieghofer
authors.affiliation: Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Laboratory of Biofunctional Imaging, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Neurology, National Hospital Organization Toneyama Hospital, Osaka, Japan.
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.affiliation: Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Shizuya
authors.initials: S
authors.lastname: Saika
authors.affiliation: Laboratory of Biofunctional Imaging, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Laboratory of Molecular Neuroscience, Graduate School of Medicine, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Osaka University, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
authors.affiliation: BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D051379:Mice; D009103:Multiple Sclerosis / Q000473:pathology*; D010146:Pain; D012008:Recurrence; D013116:Spinal Cord / Q000473:pathology
chemical_list: D018925:Chemokines
keywords: CD4 T cell-mediated disease; EAE; immunology; mouse; neural signaling; relapse