Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia.
Toll-like receptors (TLRs) are signaling receptors in the innate immune system that is a specific immunologic response to systemic bacterial infection. We investigated whether cerebral ischemia induced by the middle cerebral artery occlusion (MCAO) for 2 h differed in mice that lack a functional TLR3, TLR4, or TLR9 signaling pathway. TLR4, but not TLR3 or TLR9, knock-out (KO) mice had significantly smaller infarct area and volume at 24 h after ischemia-reperfusion (I/R) compared with wild-type mice. In addition, TLR4 KO mice improved in neurological deficits after I/R compared with wild-type mice. Moreover, we investigated the expression of TLR4 in the ischemic brain with immunohistochemistry. The number of TLR4-positive cells gradually increased from 1 h after MCAO to 22 h after I/R. We also examined the localization of TLR4 in the ischemic area. TLR4 was localized with CD11b-positive microglial cells in the ischemic striatum and the number of CD11b-positive microglial cells was smaller in TLR4 KO mice than in wild-type mice. In addition, we investigated the translocation of NF-κB among TLR3, 4, and 9 KO mice after I/R injury using western blotting. NF-κB's p65 subunit was decreased in TLR4 KO mice compared to wild-type mice, but not TLR3 or 9 KO mice. These data suggest that TLR4 knockout, but not TLR3 or TLR9 knockout, may play a neuroprotective role in ischemic brain injury induced by MCAO in mice.
Hyakkoku
K
K
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
Hamanaka
J
J
Tsuruma
K
K
Shimazawa
M
M
Tanaka
H
H
Uematsu
S
S
Akira
S
S
Inagaki
N
N
Nagai
H
H
Hara
H
H
D000818:Animals; D002545:Brain Ischemia / Q000150:complications* / Q000235:genetics; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002544:Cerebral Infarction / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009422:Nervous System Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D039481:CD11b Antigen; D010751:Phosphopyruvate Hydratase; D017346:Protein Serine-Threonine Kinases; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D000097782:NF-kappaB-Inducing Kinase; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse