Activation of Toll-Like Receptor 4 Signaling Contributes to Hippocampal Neuronal Death Following Global Cerebral Ischemia/Reperfusion
Document Type
Article
Publication Date
10-1-2007
Description
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-Ik{cyrillic}B) as well as activation of nuclear factor kappa B (NFk{cyrillic}B) increased in the HF of WT mice. In contrast, there were lower levels of p-Ik{cyrillic}B and NFk{cyrillic}B binding activity in TLR4-/- mice subjected to GCI/R. Pro-inflammatory cytokine expression was also decreased, while phosphorylation of Akt and GSK3β 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.
Citation Information
Hua, Fang; Ma, Jing; Ha, Tuanzhu; Xia, Yeling; Kelley, Jim; Williams, David L.; Kao, Race L.; William Browder, I.; Schweitzer, John B.; Kalbfleisch, John H.; and Li, Chuanfu. 2007. Activation of Toll-Like Receptor 4 Signaling Contributes to Hippocampal Neuronal Death Following Global Cerebral Ischemia/Reperfusion. Journal of Neuroimmunology. Vol.190(1-2). 101-111. https://doi.org/10.1016/j.jneuroim.2007.08.014 PMID: 17884182 ISSN: 0165-5728