title: Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects.
abstract: 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.
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain.
authors.forename: Romana
authors.identifier: 0000-0002-3374-2698
authors.initials: R
authors.lastname: Tomasoni
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Morini
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain.
authors.forename: Jose P
authors.initials: JP
authors.lastname: Lopez-Atalaya
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|IN-CNR, Milano, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Corradini
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|Hunimed University, Rozzano, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Canzi
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|Hunimed University, Rozzano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rasile
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mantovani
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|Hunimed University, Rozzano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Pozzi
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|Hunimed University, Rozzano, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|IN-CNR, Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Menna
authors.affiliation: Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Barco
authors.affiliation: IRCCS Humanitas, Rozzano, Italy.|IN-CNR, Milano, Italy.
authors.forename: Michela
authors.identifier: 0000-0002-3569-7843
authors.initials: M
authors.lastname: Matteoli
mesh_terms: D000818:Animals; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: MeCP2; Neuroimmunology; neuroscience; synaptic plasticity