2. Academic Validation
  3. Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway

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

  • EMBO Mol Med. 2010 Dec;2(12):504-15. doi: 10.1002/emmm.201000103.
Xiaoli Guo 1,  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
Affiliations

Affiliation

  • 1 Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan.
PMID: 21064192 DOI: 10.1002/emmm.201000103
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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