TY - JOUR
T1 - TLR3 preconditioning induces anti-inflammatory and anti-ictogenic effects in mice mediated by the IRF3/IFN-β axis
AU - Kostoula, C.
AU - Shaker, T.
AU - Cerovic, M.
AU - Craparotta, I.
AU - Marchini, S.
AU - Butti, E.
AU - Pascente, R.
AU - Iori, V.
AU - Garlanda, C.
AU - Aronica, E.
AU - Martino, G.
AU - Ravizza, T.
AU - Carmant, L.
AU - Vezzani, A.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Activation of Toll-like receptor 3 (TLR3) was previously shown to contribute to the generation of epileptic seizures in rodents by evoking a proinflammatory response in the forebrain. This suggests that TLR3 blockade may provide therapeutic effects in epilepsy. We report that brain activation of TLR3 using the synthetic receptor ligand Poly I:C may also result in remarkable dose- and time-dependent inhibitory effects on acute seizures in mice without inducing inflammation. These inhibitory effects are associated with reduced neuronal excitability in the hippocampus as shown by a decrease in the population spike amplitude of CA1 pyramidal neurons following Schaffer collaterals stimulation. TLR3 activation which results in seizure inhibition does not evoke NF-kB-dependent inflammatory molecules or morphological activation of glia, however, it induces the alternative interferon (IFN) regulatory factor (IRF)-3/IFN-β signaling pathway. IFN-β reproduced the inhibitory effects of Poly I:C on neuronal excitability in hippocampal slices. Seizure inhibition attained with activation the TLR3-IRF3/IFN-β axis should be carefully considered when TLR3 are targeted for therapeutic purposes.
AB - Activation of Toll-like receptor 3 (TLR3) was previously shown to contribute to the generation of epileptic seizures in rodents by evoking a proinflammatory response in the forebrain. This suggests that TLR3 blockade may provide therapeutic effects in epilepsy. We report that brain activation of TLR3 using the synthetic receptor ligand Poly I:C may also result in remarkable dose- and time-dependent inhibitory effects on acute seizures in mice without inducing inflammation. These inhibitory effects are associated with reduced neuronal excitability in the hippocampus as shown by a decrease in the population spike amplitude of CA1 pyramidal neurons following Schaffer collaterals stimulation. TLR3 activation which results in seizure inhibition does not evoke NF-kB-dependent inflammatory molecules or morphological activation of glia, however, it induces the alternative interferon (IFN) regulatory factor (IRF)-3/IFN-β signaling pathway. IFN-β reproduced the inhibitory effects of Poly I:C on neuronal excitability in hippocampal slices. Seizure inhibition attained with activation the TLR3-IRF3/IFN-β axis should be carefully considered when TLR3 are targeted for therapeutic purposes.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85069837434&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31336144
U2 - https://doi.org/10.1016/j.bbi.2019.07.021
DO - https://doi.org/10.1016/j.bbi.2019.07.021
M3 - Article
C2 - 31336144
SN - 0889-1591
VL - 81
SP - 598
EP - 607
JO - Brain, behavior, and immunity
JF - Brain, behavior, and immunity
ER -