Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion

J Neuroimmunol. 2007 Oct;190(1-2):101-11. doi: 10.1016/j.jneuroim.2007.08.014. Epub 2007 Sep 19.

Abstract

Toll-like receptors (TLRs) play a critical role in the induction of innate immune responses which have been implicated in neuronal death induced by global cerebral ischemia/reperfusion (GCI/R). The present study investigated the role and mechanisms-of-action of TLR4 signaling in ischemia-induced hippocampal neuronal death. Neuronal damage, activation of the TLR4 signaling pathway, expression of pro-inflammatory cytokines and activation of the PI3K/Akt signaling pathway in the hippocampal formation (HF) were assessed in wild type (WT) mice and TLR4 knockout (TLR4(-/-)) mice after GCI/R. GCI/R increased expression of TLR4 protein in the hippocampal formation (HF) and other brain structures in WT mice. Phosphorylation of the inhibitor of kappa B (p-IkappaB) as well as activation of nuclear factor kappa B (NFkappaB) increased in the HF of WT mice. In contrast, there were lower levels of p-IkappaB and NFkappaB binding activity in TLR4(-/-) mice subjected to GCI/R. Pro-inflammatory cytokine expression was also decreased, while phosphorylation of Akt and GSK3beta were increased in the HF of TLR4(-/-) mice after GCI/R. These changes correlated with decreased neuronal death/apoptosis in TLR4(-/-) mice following GCI/R. These data suggest that activation of TLR4 signaling contributes to ischemia-induced hippocampal neuronal death. In addition, these data suggest that modulation of TLR4 signaling may attenuate ischemic injury in hippocampal neurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / immunology*
  • Brain Ischemia / metabolism
  • Brain Ischemia / physiopathology
  • Cell Death / drug effects
  • Cell Death / immunology
  • Cerebral Infarction / immunology*
  • Cerebral Infarction / metabolism
  • Cerebral Infarction / physiopathology
  • Cytokines / metabolism
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / immunology*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • I-kappa B Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Nerve Degeneration / immunology*
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reperfusion Injury / immunology*
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / physiopathology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology*
  • Up-Regulation / genetics
  • Up-Regulation / immunology

Substances

  • Cytokines
  • I-kappa B Proteins
  • NF-kappa B
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3