• Open Access

Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway

Authors

  • Xiaoli Guo,

    1. Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan
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  • Chikako Harada,

    1. Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan
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  • Kazuhiko Namekata,

    1. Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan
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  • Atsushi Matsuzawa,

    1. Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Global Center of Excellence Program, Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, The University of Tokyo, Tokyo, Japan
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  • Monsterrat Camps,

    1. Department of Inflammation, Merck Serono International S.A., Chemin de Mines, Geneva, Switzerland
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  • Hong Ji,

    1. Department of Early PK/PD, Merck Serono International S.A., Chemin de Mines, Geneva, Switzerland
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  • Dominique Swinnen,

    1. Department of Chemistry, Merck Serono International S.A., Chemin de Mines, Geneva, Switzerland
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  • Catherine Jorand-Lebrun,

    1. Department of Chemistry, Merck Serono International S.A., Chemin de Mines, Geneva, Switzerland
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  • Mathilde Muzerelle,

    1. Department of Chemistry, Merck Serono International S.A., Chemin de Mines, Geneva, Switzerland
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  • Pierre-Alain Vitte,

    1. Department of Early PK/PD, Merck Serono International S.A., Chemin de Mines, Geneva, Switzerland
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  • Thomas Rückle,

    1. Department of Chemistry, Merck Serono International S.A., Chemin de Mines, Geneva, Switzerland
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  • Atsuko Kimura,

    1. Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan
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  • Kuniko Kohyama,

    1. Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan
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  • Yoh Matsumoto,

    1. Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan
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  • Hidenori Ichijo,

    1. Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, Global Center of Excellence Program, Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, The University of Tokyo, Tokyo, Japan
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  • Takayuki Harada

    Corresponding author
    1. Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan
    • Tel: +81 42 325 3881; Fax: +81 42 321 8678
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Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll-like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1-p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small molecular weight inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis.

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