Open AccessRegulation of the severity of neuroinflammation and demyelination by TLR‐ASK1‐p38 pathway
Author(s) -
Guo Xiaoli,
Harada Chikako,
Namekata Kazuhiko,
Matsuzawa Atsushi,
Camps Monsterrat,
Ji Hong,
Swinnen Dominique,
JorandLebrun Catherine,
Muzerelle Mathilde,
Vitte PierreAlain,
Rückle Thomas,
Kimura Atsuko,
Kohyama Kuniko,
Matsumoto Yoh,
Ichijo Hidenori,
Harada Takayuki
Publication year - 2010
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201000103
Subject(s) - ask1 , neuroinflammation , experimental autoimmune encephalomyelitis , p38 mitogen activated protein kinases , microglia , microbiology and biotechnology , mapk/erk pathway , immunology , protein kinase a , signal transduction , inflammation , kinase , chemokine , biology , cancer research , mitogen activated protein kinase kinase
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.