Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia

Neuroscience. 2010 Nov 24;171(1):258-67. doi: 10.1016/j.neuroscience.2010.08.054. Epub 2010 Sep 16.

Abstract

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.

MeSH terms

  • Animals
  • Brain Ischemia / complications*
  • Brain Ischemia / genetics
  • CD11b Antigen / metabolism
  • Cell Count / methods
  • Cerebral Infarction / etiology*
  • Cerebral Infarction / pathology
  • Cerebral Infarction / prevention & control*
  • Disease Models, Animal
  • Gene Expression Regulation / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappaB-Inducing Kinase
  • Nervous System Diseases / etiology*
  • Nervous System Diseases / pathology
  • Nervous System Diseases / prevention & control*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphopyruvate Hydratase / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Statistics, Nonparametric
  • Time Factors
  • Toll-Like Receptor 3 / deficiency
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / deficiency*
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / metabolism

Substances

  • CD11b Antigen
  • TLR3 protein, mouse
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Protein Serine-Threonine Kinases
  • Phosphopyruvate Hydratase