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

Xiaoli Guo, Chikako Harada, Kazuhiko Namekata, Atsushi Matsuzawa, Monsterrat Camps, Hong Ji, Dominique Swinnen, Catherine Jorand-Lebrun, Mathilde Muzerelle, Pierre Alain Vitte, Thomas Rückle, Atsuko Kimura, Kuniko Kohyama, Yoh Matsumoto, Hidenori Ichijo, Takayuki Harada

Research output: Contribution to journalArticlepeer-review

117 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)504-515
Number of pages12
JournalEMBO Molecular Medicine
Issue number12
Publication statusPublished - 2010 Dec


  • ASK1
  • Chemokines
  • Demyelination
  • Glia
  • Toll-like receptors


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