TLR3 preconditioning induces anti-inflammatory and anti-ictogenic effects in mice mediated by the IRF3/IFN-β axis: Brain, Behavior, and Immunity

C Kostoula, T Shaker, M Cerovic, I Craparotta, S Marchini, E Butti, R Pascente, V Iori, C Garlanda, E Aronica, G Martino, T Ravizza, L Carmant, A Vezzani

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Abstract

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. © 2019
Original languageEnglish
Pages (from-to)598-607
Number of pages10
JournalBrain Behav. Immun.
Volume81
DOIs
Publication statusPublished - 2019

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Kostoula, C., Shaker, T., Cerovic, M., Craparotta, I., Marchini, S., Butti, E., Pascente, R., Iori, V., Garlanda, C., Aronica, E., Martino, G., Ravizza, T., Carmant, L., & Vezzani, A. (2019). TLR3 preconditioning induces anti-inflammatory and anti-ictogenic effects in mice mediated by the IRF3/IFN-β axis: Brain, Behavior, and Immunity. Brain Behav. Immun., 81, 598-607. https://doi.org/10.1016/j.bbi.2019.07.021