Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects

Inflammation modifies risk and/or severity of a variety of brain diseases through still elusive molecular mechanisms. Here we show that hyperactivation of the interleukin 1 pathway, through either ablation of the interleukin 1 receptor 8 (IL-1R8, also known as SIGIRR or Tir8) or activation of IL-1R,...

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Bibliographic Details
Published in:eLife 2017-03, Vol.6
Main Authors: Tomasoni, Romana, Morini, Raffaella, Lopez-Atalaya, Jose P, Corradini, Irene, Canzi, Alice, Rasile, Marco, Mantovani, Cristina, Pozzi, Davide, Garlanda, Cecilia, Mantovani, Alberto, Menna, Elisabetta, Barco, Angel, Matteoli, Michela
Format: Article
Language:English
Subjects:
Ablation
Animals
Cognitive ability
Cytokines
Defects
Dendritic plasticity
Dendritic spines
Gene expression
Genetic engineering
Health aspects
Immune response
Immune system
Interleukin 1
Interleukin 1 receptor antagonist
Interleukin 1 receptors
Interleukins
MeCP2
MeCP2 protein
Methyl-CpG binding protein
Methyl-CpG-Binding Protein 2 - metabolism
Mice
Mice, Knockout
Molecular modelling
Morphology
Neural circuitry
Neuroimmunology
Neurological diseases
Neurons - physiology
Neuroscience
Proteins
Receptors, Interleukin-1 - deficiency
Receptors, Interleukin-1 - genetics
Receptors, Interleukin-1 - metabolism
Rodents
Signal Transduction
Software
Statistical analysis
Synaptic plasticity
TOR protein
TOR Serine-Threonine Kinases - metabolism
Transcription activation
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Summary:Inflammation modifies risk and/or severity of a variety of brain diseases through still elusive molecular mechanisms. Here we show that hyperactivation of the interleukin 1 pathway, through either ablation of the interleukin 1 receptor 8 (IL-1R8, also known as SIGIRR or Tir8) or activation of IL-1R, leads to up-regulation of the mTOR pathway and increased levels of the epigenetic regulator MeCP2, bringing to disruption of dendritic spine morphology, synaptic plasticity and plasticity-related gene expression. Genetic correction of MeCP2 levels in IL-1R8 KO neurons rescues the synaptic defects. Pharmacological inhibition of IL-1R activation by Anakinra corrects transcriptional changes, restores MeCP2 levels and spine plasticity and ameliorates cognitive defects in IL-1R8 KO mice. By linking for the first time neuronal MeCP2, a key player in brain development, to immune activation and demonstrating that synaptic defects can be pharmacologically reversed, these data open the possibility for novel treatments of neurological diseases through the immune system modulation.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.21735