1. Immunology and Inflammation
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A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model

  1. Yasunobu Arima
  2. Daisuke Kamimura
  3. Toru Atsumi
  4. Masaya Harada
  5. Tadafumi Kawamoto
  6. Naoki Nishikawa
  7. Andrea Stofkova
  8. Takuto Ohki
  9. Kotaro Higuchi
  10. Yuji Morimoto
  11. Peter Wieghofer
  12. Yuka Okada
  13. Yuki Mori
  14. Saburo Sakoda
  15. Shizuya Saika
  16. Yoshichika Yoshioka
  17. Issei Komuro
  18. Toshihide Yamashita
  19. Toshio Hirano
  20. Marco Prinz
  21. Masaaki Murakami  Is a corresponding author
  1. Hokkaido University, Japan
  2. Tsurumi University, Japan
  3. University of Freiburg, Germany
  4. Wakayama Medical University, Japan
  5. Osaka University, Japan
  6. National Hospital Organization Toneyama Hospital, Japan
  7. University of Tokyo, Japan
Research Article
  • Cited 32
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Cite this article as: eLife 2015;4:e08733 doi: 10.7554/eLife.08733

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.

Article and author information

Author details

  1. Yasunobu Arima

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Daisuke Kamimura

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Toru Atsumi

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Masaya Harada

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Tadafumi Kawamoto

    Department of Dentistry, Tsurumi University, Yokohama, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Naoki Nishikawa

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrea Stofkova

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Takuto Ohki

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Kotaro Higuchi

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Yuji Morimoto

    Department of Anesthesiology and Critical Care Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Peter Wieghofer

    Institute of Neuropathology, Faculty of Biology, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Yuka Okada

    Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan
    Competing interests
    The authors declare that no competing interests exist.
  13. Yuki Mori

    Laboratory of Biofunctional Imaging, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  14. Saburo Sakoda

    Department of Neurology, National Hospital Organization Toneyama Hospital, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  15. Shizuya Saika

    Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan
    Competing interests
    The authors declare that no competing interests exist.
  16. Yoshichika Yoshioka

    Laboratory of Biofunctional Imaging, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  17. Issei Komuro

    Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  18. Toshihide Yamashita

    Laboratory of Molecular Neuroscience, Graduate School of Medicine, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  19. Toshio Hirano

    Osaka University, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  20. Marco Prinz

    BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  21. Masaaki Murakami

    Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
    For correspondence
    murakami@igm.hokudai.ac.jp
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal experiments were performed following the guidelines of the Institutional Animal Care and Use Committees of the Institute for Genetic Medicine, the Graduate School of Medicine, Hokkaido University and the Graduate School of Frontier Bioscience and Graduate School of Medicine, Osaka University with protocol numbers 2014-0083 and 2014-0026.

Reviewing Editor

  1. Satyajit Rath, National Institute of Immunology, India

Publication history

  1. Received: May 14, 2015
  2. Accepted: July 14, 2015
  3. Accepted Manuscript published: July 20, 2015 (version 1)
  4. Version of Record published: August 11, 2015 (version 2)

Copyright

© 2015, Arima et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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