Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperToll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia
Section snippets
Experimental materials
The experiments were conducted in accordance with the Animal Care Guidelines issued by the Animal Experiments Committee of Gifu Pharmaceutical University. All efforts were made to minimize both suffering and the number of animals used. The TLR3 KO and TLR9 KO mice were backcrossed nine generation onto a BALB/c background. TLR4 KO mice were backcrossed nine generation onto a C57BL/6 background or a BALB/c background. The animals were housed at 24±2 °C under a 12 h light-dark cycle (lights on
Physiological parameters
There were no significant differences in mean arterial blood pressure (MABP) or heart rate (HR), in arterial pH, pCO2, pO2, or in rCBF between the wild-type and TLR4 KO mice (data not shown). Surface rCBF was reduced to approximately 20% of the baseline value immediately after MCAO in all mice (data not shown).
Infarction and neurological deficits after ischemia
Twenty-four hours after I/R, mice developed infarcts affecting the cortex and striatum (Fig. 1, Fig. 2). TLR4 KO mice had significantly smaller infarct area and volume at 24 h after MCAO
Discussion
The main aim of this study was to investigate the stroke outcomes of TLR3, TLR4, or TLR9 KO mice. The present study showed that TLR4 KO mice have smaller cerebral infarctions compared with wild-type mice. On the other hand, in TLR3 KO and TLR9 KO mice, there were no significant differences in stroke outcomes (infarct area, infarct volume, or neurological deficits), suggesting that TLR3 or TLR9 signaling pathway is not directly related to ischemic brain injury induced by I/R. Activation of TLRs
Conclusion
In conclusion, TLR4, but not TLR3 or TLR9, KO mice showed a neuroprotective effect on the neuronal damage and neurological deficits after ischemia, and TLR4 was up-regulated in response to ischemia-reperfusion in the brain, suggesting that TLR4 may play a pivotal role in the pathogenesis of the ischemic brain damage induced by MCAO.
Acknowledgments
The authors thank Dr. Tsuyoshi Sugiyama (Microbiology, Gifu Pharmaceutical University) for technical support.
References (38)
- et al.
Reduced cerebral ischemia-reperfusion injury in toll-like receptor 4 deficient mice
Biochem Biophys Res Commun
(2007) - et al.
Microglia: intrinsic immuneffector cell of the brain
Brain Res Brain Res Rev
(1995) - et al.
Species-specific regulation of toll-like receptor 3 genes in men and mice
J Biol Chem
(2003) - et al.
Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice
Brain Res
(2009) - et al.
The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice
Biochem Biophys Res Commun
(2009) - et al.
MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression
FEBS Lett
(2003) - et al.
Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia
J Neuroimmunol
(2007) - et al.
PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human toll-like receptor 4 gene
J Biol Chem
(2000) - et al.
IL-10 reduces rat brain injury following focal stroke
Neurosci Lett
(1998) - et al.
TLR2 has a detrimental role in mouse transient focal cerebral ischemia
Biochem Biophys Res Commun
(2007)
TLR signaling
Curr Top Microbiol Immunol
Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition
Proc Natl Acad Sci U S A
Differential activation of astrocytes by innate and adaptive immune stimuli
Glia
Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke
Stroke
Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke
Circulation
Mal (MyD88-adapter-like) is required for toll-like receptor-4 signal transduction
Nature
Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system
J Neurosci Res
Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein
J Cereb Blood Flow Metab
Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage
Proc Natl Acad Sci U S A
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2022, Brain, Behavior, and ImmunityCitation Excerpt :Microglial TLR4 expression was upregulated as early as 4 h post ischemia/reperfusion whereas neuronal TLR4 was unaltered at this time. Increased neuronal TLR4 expression was not evident until a later time-22 h post ischemia/reperfusion (Hyakkoku et al., 2010). Taken together, the studies suggest that the detrimental outcomes of TLR2 and TLR4 activation on neuronal viability and tissue damage following ischemia/reperfusion are mediated by both microglial and neuronal TLR2 and TLR4, acting at different times post-ischemia.
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These authors contributed equally.