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

doi:10.1002/emmm.201000103

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.

Authors

Xiaoli Guo¹, 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

Affiliation

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

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Diseases / drug therapy
Brain Diseases / genetics
Brain Diseases / immunology
Brain Diseases / metabolism
Chemokines / immunology
Demyelinating Diseases / drug therapy
Demyelinating Diseases / genetics
Demyelinating Diseases / immunology
Demyelinating Diseases / metabolism*
Disease Models, Animal
Encephalitis
Enzyme Inhibitors / administration & dosage
Female
Gene Expression Regulation
Hashimoto Disease / drug therapy
Hashimoto Disease / genetics
Hashimoto Disease / immunology
Hashimoto Disease / metabolism
Humans
MAP Kinase Kinase Kinase 5 / antagonists & inhibitors
MAP Kinase Kinase Kinase 5 / genetics
MAP Kinase Kinase Kinase 5 / metabolism*
Male
Mice
Mice, Inbred C57BL
Neuroglia / metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction*
Toll-Like Receptors / genetics
Toll-Like Receptors / metabolism*
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Chemokines
Enzyme Inhibitors
Toll-Like Receptors
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase Kinase 5

Supplementary concepts

Hashimoto's encephalitis