Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway.
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.
Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo Metropolitan Organization for Medical Research, Fuchu, Tokyo, Japan.
Xiaoli
X
Guo
Chikako
C
Harada
Kazuhiko
K
Namekata
Atsushi
A
Matsuzawa
Monsterrat
M
Camps
Hong
H
Ji
Dominique
D
Swinnen
Catherine
C
Jorand-Lebrun
Mathilde
M
Muzerelle
Pierre-Alain
PA
Vitte
Thomas
T
Rückle
Atsuko
A
Kimura
Kuniko
K
Kohyama
Yoh
Y
Matsumoto
Hidenori
H
Ichijo
Takayuki
T
Harada
D000818:Animals; D001927:Brain Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000276:immunology; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005786:Gene Expression Regulation; D050031:Hashimoto Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D004791:Enzyme Inhibitors; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5