TY - JOUR
T1 - Lack of IL-1r8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects
AU - Tomasoni, Romana
AU - Morini, Raffaella
AU - Lopez-Atalaya, Jose P.
AU - Corradini, Irene
AU - Canzi, Alice
AU - Rasile, Marco
AU - Mantovani, Cristina
AU - Pozzi, Davide
AU - Garlanda, Cecilia
AU - Mantovani, Alberto
AU - Menna, Elisabetta
AU - Barco, Angel
AU - Matteoli, Michela
PY - 2017/3/28
Y1 - 2017/3/28
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.21735
DO - 10.7554/eLife.21735
M3 - Article
C2 - 28347403
AN - SCOPUS:85017178144
VL - 6
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e21735
ER -