Errors that occur while the brain is developing can lead to conditions such as autism and schizophrenia. They can also lead to rare disorders like Rett syndrome and MeCP2 duplication syndromes, which are characterized by severe cognitive and physical disabilities. Many people with these neurodevelopmental disorders have mutations in genes that encode proteins found at synapses, which are the junctions between neurons where the cells exchange information with one another. However, not everyone with these mutations develops a neurodevelopmental disorder, which indicates that other, non-genetic factors also play a part.

One of the main non-genetic factors that can influence the risk and severity of neurodevelopmental disorders is inflammation of the brain. Inflammation is a normal part of the body’s immune response to threats such as invading microorganisms or tissue damage. However, abnormal activation of the immune system in early life can trigger excessive inflammation. This increases the risk of a neurodevelopmental disorder, but it is not clear exactly how it does so.

Tomasoni et al. set out to test whether the missing link between inflammation and neurodevelopmental disorders might be damage to synapses. The experiments revealed that genetically modified mice with inflammation of the brain have abnormal synapses and are unable to learn properly. These mutant mice also have excessive levels of a protein that influences how synapses function called MeCP2, which is missing in the brains of people with Rett syndrome and abnormally increased in brains of patients affected by MeCP2 Duplication Syndrome. This is thus the first evidence that directly links inflammation of the brain to a synapse protein implicated in a disorder of brain development.

Tomasoni et al. also found that a drug called anakinra – which is used to treat an inflammatory disease called rheumatoid arthritis – reduced levels of MeCP2 in the mutant mice and improved their performance in cognitive tasks. Together, these results raise the possibility that anti-inflammatory medications may be beneficial in the treatment of neurodevelopment disorders.

Neurological disorders represent an enormous source of burden to the individual and to society, with many patients failing to respond to available medication. Growing evidence on genetic components of neurological diseases have been collected during recent years; notably, these genes overwhelmingly point to disorders of synaptic transmission, which led to the coinage of the term ‘synaptopathy’ to indicate a brain disease originating from a dysfunction of the synapse (Grant, 2012; Grabrucker, 2014). Disruption of synapse function may also be caused by environmental stimuli, with inflammatory cytokines affecting synaptic transmission and modifying the risk and severity of a variety of brain diseases, including autism spectrum disorders, schizophrenia and cognitive disabilities (Hagberg et al., 2012; Chugh et al., 2013; Steinman, 2013). Among the cytokines known to affect synaptic function, the proinflammatory cytokine IL-1β plays a critical role. IL-1β was found to impair brain-derived neurotrophic factor (BDNF)-induced expression of molecules critical for activity-dependent synaptic plasticity, including cAMP response element binding protein (CREB), Arc, and cofilin, thus reducing actin polymerization and impairing spine morphogenesis (Tong et al., 2012). In addition, IL-1β controls different neuronal functions, including excitability and transmitter release, via multiple biochemical pathways (Weber et al., 2010). However, no evidence has been reported yet that IL-1β may affect synapse development and function acting on molecular pathways known to be at the root of synaptopathies.

Genetic mouse models of immune deregulation may serve as reliable and reproducible systems for examination of the effects of inflammation on synapse structure and function and elucidation of the molecular processes involved. IL-1R8, also known as single Ig IL-1-Related Receptor (SIGIRR) or TIR8, belongs to the toll-like receptors (TLRs) and interleukin-1R-like receptors (ILRs), a family of conserved proteins involved in immunity and inflammation (Riva et al., 2012; Garlanda et al., 2013a). TLRs are receptors able to recognize specific pathogen-associated patterns (PAMPs) and necrotic cell-derived danger signals (DAMPs) and act as sensors for microorganisms and tissue damage, whereas the IL-1R subfamily includes components of signalling receptor complexes as well as molecules with regulatory function. IL-1R8 dampens the activation of the TLRs and IL-1R signalling pathways by intracellularly interfering with the association of adaptor molecules to the receptor complexes, including NF-κB and JNK (Riva et al., 2012; Garlanda et al., 2013b). As a consequence, IL-1R8-deficient mice display exaggerated symptoms of inflammatory conditions (Garlanda et al., 2007; Gulen et al., 2010; Drexler et al., 2010) and demonstrate pronounced susceptibility to the inflammatory challenge posed by microbial LPS (Garlanda et al., 2004). IL-1R8 is also present in the brain (Costelloe et al., 2008; Polentarutti et al., 2003). Genetic deficiency for IL-1R8 is associated with inflammatory changes in the brain, including increased levels of LPS-induced tumor necrosis factor α (TNFα) and IL-6 in microglia, higher expression of TLR4, and NF-κB activation (Watson et al., 2010). Reduced IL-1R8 expression has been described in patients affected by psoriatic arthritis (Batliwalla et al., 2005) while SIGIRR variants (characterized by defective SIGIRR function) have been found in humans in association with necrotizing enterocolitis (Sampath et al., 2015) and with systemic lupus erythematosus (SLE; [Zhu et al., 2014]), all pathologies being characterized by cognitive defects and neurodevelopmental impairment (Husted et al., 2013; Rees et al., 2007; Calderón et al., 2014; Muscal et al., 2010). Notably, IL-1R8-deficient mice are impaired in novel object recognition, spatial reference memory and long-term potentiation (LTP), defects that occur in the absence of any external inflammatory stimuli (Costello et al., 2011). However, the molecular mechanisms by which IL-1R8 deficiency results in brain defects are still completely unknown.

We used IL-1R8 deficient mice to investigate whether genetic hyperactivation of the IL-1R pathway affects synapse function impinging on molecular players involved in synaptopathies. We demonstrate that the activity of the IL-1R pathway directly affects, in neurons, the levels of expression of the methyl-CpG-binding protein 2 (MeCP2), a synaptopathy protein involved in neurological diseases -Rett syndrome and MeCP2 duplication syndrome- characterized by defective plasticity, impaired cognition and intellectual disability. We also show that pharmacological inhibition of IL-1R activity normalizes MeCP2 expression and cognitive deficits in IL1R8-deficient mice.

Finely tuned expression of immune molecules has been found to modulate CNS function (Deverman and Patterson, 2009), both throughout normal development and in pathological conditions. During development, immune molecules such as CXCR4, interferon γ, IL-1β, IL-6, IL-9, IL-10 and transforming growth factor β affect neurogenesis, neuronal migration, axon guidance, synapse formation, activity-dependent refinement of circuits and synaptic plasticity (Deverman and Patterson, 2009; Zhao and Schwartz, 1998). In line with this concept, mice genetically devoid of IL-1R8, a receptor which dampens the activation of the TLRs and IL-1R signalling pathways, are neurologically impaired, showing defects in novel place recognition task, spatial reference memory and LTP, defects that occur in the absence of any external inflammatory stimuli (Costello et al., 2011). However, the molecular processes at the basis of these defects are still elusive.

Our study provides two major breakthroughs in the field of the cross talk between nervous and immune systems: first, it demonstrates that hyperactivation of the IL1R pathway results in the overexpression of MeCP2, a synaptic factor that controls spine morphogenesis, synaptic transmission and plasticity, which is responsible for syndromes associated with intellectual disability such as Rett syndrome and MeCP2 duplication syndrome; second it provides the proof-of-concept that the synaptic and behavioral defects consequent to genetic hyperactivation of the IL-1R pathway can be rescued in the adult by pharmacological treatment with IL-1Ra. Of note, the acute application of IL-1β to mature neurons recapitulates similar synaptic defects and alterations of MeCP2 expression. Consistently, transcriptomic analysis of cortices from WT mice (treated or not with IL-1β) and from IL-1R8 KO animals (treated or not treated with Anakinra) show that a common set of genes is transcriptionally altered in WT mice treated with IL-1β and in IL-1R8 KO animals, including genes controlling synaptic function and spine morphogenesis. The expression of this set of genes is restored to normal levels by treatment with Anakinra in IL-1R8 KO mice. These findings have important repercussions in the clinic, as they could open the road to the use of anti-inflammatory drugs as therapeutic treatments for neuropsychiatric illnesses such as schizophrenia, autism and mental retardation, for all of which an immune component has been demonstrated (Khandaker et al., 2015; Theoharides et al., 2015; Young et al., 2016).

Our study identifies the crucial involvement of the AKT/mTOR pathway in IL-1R8 KO neurons (Figure 10H). IL-1R8 has been previously reported to regulate mTOR kinase activity in Th17 cells, playing a nonredundant role in controlling mTOR-dependent differentiation, proliferation and cytokine production (Gulen et al., 2010). The demonstration that the PI3K/Akt/mTOR pathway is at the root of synaptic defects in IL-1R8 KO neurons is in line with the established involvement of this pathway in dendritic tree development and spine formation in neurons (Sarbassov et al., 2006), as well as actin cytoskeleton dynamics and synaptic plasticity (Jaworski and Sheng, 2006). Remarkably, the mTOR pathway is closely linked to ILR/TLR signaling since PI3 kinase is required for activation of NF-κB by IL-1 (Gulen et al., 2010). Furthermore, the signaling module containing the MyD88 adaptor protein, together with phosphorylated IRAK and TRAF6, which is downstream to both IL-1R and TLRs activation, is essential for PI3K recruitment and Akt activation, making mTOR one of the downstream targets of ILR/TLRs signaling (Gulen et al., 2010). Consistent with the involvement of mTOR in the IL-1R8 KO neuron defects, treatment with the PI3 kinase inhibitors, LY294002 and wortmannin restored the neuronal ability to sustain LTP. Moreover, specific inhibition of mTOR by the drug rapamycin rescues synaptic morphology in IL-1R8 KO neurons. These results indicate that the PI3K-regulated pathway is involved in the downstream signaling that connects excessive IL-1R activation to the morphological and functional impairments of dendritic spines observed in IL-1R8 KO neurons.

More importantly, our study shows for the first time that activation of IL-1R in neurons increases the levels of MeCP2, both in vitro and in vivo. Fine-tuning of MeCP2 expression is required for proper synapse function (reviewed in Na et al. [2013]). Indeed, lack of expression of MeCP2 results in deceleration of body and head growth rate, problems in motor and speech capabilities, irregularities in motor activity and difficulties in breathing, and also in cognitive defects characteristic of an autism-spectrum disorder (reviewed in Percy and Lane [2005]). Mouse models of MeCP2 duplication display a neurological phenotype, stereotyped and repetitive movements, epilepsy, spasticity, hypoactivity, early death (Collins et al., 2004) and defects in dendritic arborization and spine morphology (Jiang et al., 2013). In humans, sporadic mutations in the gene coding for MeCP2 results in Rett syndrome (Amir et al., 1999), while a double dosage of MeCP2 causes a severe developmental delay and mental retardation (Lubs et al., 1999). Thus, MeCP2 levels must be finely tuned as even mild over-expression of this factor can have a robust effect. We first demonstrate here that immune activation controls the expression of MeCP2 in neurons. The possibility that MeCP2 phosphorylation, by which MeCP2 also modulates gene expression levels, is altered in these models is an open issue. MeCP2 can act as a transcriptional activator (when interacting with CREB) but primarily functions as a transcriptional repressor associated with mSin3A and HDACs repressor complexes (Chahrour et al., 2008; Jones et al., 1998; Nan et al., 1998). Consistently, we observed a prevalence of downregulation over upregulation in the expression of the deregulated genes in WT mice treated with IL-1β and in IL-1R8 KO animals, suggesting that the repressor function of MeCP2 might dominate in response to IL-1R activity. Indeed, gene ontology enrichment analysis for the deregulated genes highlighted negative regulation of transcription from RNA polymerase II promoter and negative regulation of gene expression among the most affected biological processes in IL-1R8 KO animals (Supplementary file 4).

The regulation of MeCP2 protein levels by IL-1R8 appears to result from enhanced activity of IL-1R. IL-1β is a fundamental factor of inflammatory responses in the brain. It is expressed at baseline levels in the healthy brain, and its expression increases following peripheral infection, surgery, or brain injury, as well as in neurodegenerative diseases (Rothwell and Luheshi, 2000). Increases in IL-1β levels lead to cognitive decline, in particular in hippocampal-dependent tasks (Rachal Pugh et al., 2001). IL-1β overexpression for two weeks in an inducible transgenic mouse was found to cause impairment in long-term contextual and spatial memory, without effects on short-term and non-hippocampal memory (Hein et al., 2010). An increase in IL-1β levels due to Escherichia coli infection leads to defects in contextual fear conditioning, with loss of memory prevented by IL1Ra (Barrientos et al., 2009; Frank et al., 2010). Remarkably, we show that neuron treatment with IL-1β not only leads to an increase in immature spines unable to undergo LTP, but also augments MeCP2 levels. In this context, as with E. coli infection, IL1Ra/Anakinra restores synaptic function.

Our demonstration that enhanced IL-1R activity, due to either lack of IL-1R8 or excessive IL-1β signaling, impacts synapse function through regulating the expression of MeCP2 expands in a critical way previous research on the role of MeCP2 in cognition (Na et al., 2013): we show here that MeCP2 is a fundamental node linking inflammation with synaptic damage and we demonstrate that inhibition of IL-1R pathway by IL-1Ra restores synaptic structure and function in vitro. We also demonstrate that the acute treatment with Anakinra, a pharmacological agent currently in use to treat chronic inflammation, restores synaptic plasticity in vivo. Although we do not have the proof that this occurs exclusively through MeCP2 reduction, our data indicate that immune drugs may be efficacious for treating neurological deficits associated with immune pathologies with a genetic basis and justify further research into anti-inflammatory treatment for selected brain pathologies. Indeed, recurrent infections have been found to occur in 70% of individuals affected by MeCP2 duplication syndrome, which lead to further deterioration of the general and neurological status, being even fatal in some patients (van Esch et al., 2012). Also, in patients affected by cryopyrin-associated periodic syndrome (CAPS), a group of rare autoinflammatory diseases with genetic basis, the levels of IL-1β are fivefold higher than in healthy individuals, leading to persistent unregulated systemic inflammation (Janssen et al., 2004; Lachmann et al., 2009). CAPS is characterized by recurrent bouts of fever with malaise and chills, urticarial neutrophilic, eye redness due to conjunctivitis, arthralgia and myalgia with intense fatigue. Children affected by CAPS are believed to show symptoms of intellectual disability. Mental and hearing defects are reversed following treatment with Anakinra (Goldbach-Mansky, 2011; Goldbach-Mansky et al., 2006; Lepore et al., 2010; Miyamae et al., 2010; Neven et al., 2010) and with specific neutralization of IL-1β with canakinumab. Our study opens the possibility that further cognitive deterioration may result from the enhanced inflammation and hyperactivation of the IL-1 signaling pathway, which might further increase MeCP2 levels in a harmful positive feedback loop. The challenging possibility that treatment with Anakinra may help interrupting this spiral and ameliorating the cognitive deficits in affected individuals is worth to be tested.

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Author details

1. Romana Tomasoni

   1. IRCCS Humanitas, Rozzano, Italy
   2. Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain

   Contribution

   RT, Conceptualization, Data curation, Formal analysis, Investigation, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-3374-2698

2. Raffaella Morini

   IRCCS Humanitas, Rozzano, Italy

   Contribution

   RM, Data curation, Formal analysis, Investigation

   Competing interests

   The authors declare that no competing interests exist.

3. Jose P Lopez-Atalaya

   Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain

   Contribution

   JPL-A, Conceptualization, Data curation, Formal analysis

   Competing interests

   The authors declare that no competing interests exist.

4. Irene Corradini

   1. IRCCS Humanitas, Rozzano, Italy
   2. IN-CNR, Milano, Italy

   Contribution

   IC, Data curation, Formal analysis, Investigation

   Competing interests

   The authors declare that no competing interests exist.

5. Alice Canzi

   1. IRCCS Humanitas, Rozzano, Italy
   2. Hunimed University, Rozzano, Italy

   Contribution

   AC, Data curation, Formal analysis, Investigation

   Competing interests

   The authors declare that no competing interests exist.

6. Marco Rasile

   1. IRCCS Humanitas, Rozzano, Italy
   2. Hunimed University, Rozzano, Italy

   Contribution

   MR, Data curation, Formal analysis, Investigation

   Competing interests

   The authors declare that no competing interests exist.

7. Cristina Mantovani

   IRCCS Humanitas, Rozzano, Italy

   Contribution

   CM, Data curation, Formal analysis, Investigation

   Competing interests

   The authors declare that no competing interests exist.

8. Davide Pozzi

   1. IRCCS Humanitas, Rozzano, Italy
   2. Hunimed University, Rozzano, Italy

   Contribution

   DP, Data curation, Formal analysis, Investigation

   Competing interests

   The authors declare that no competing interests exist.

9. Cecilia Garlanda

   IRCCS Humanitas, Rozzano, Italy

   Contribution

   CG, Conceptualization, Writing—original draft, Writing—review and editing

   Competing interests

   The authors declare that no competing interests exist.

10. Alberto Mantovani

    1. IRCCS Humanitas, Rozzano, Italy
    2. Hunimed University, Rozzano, Italy

    Contribution

    AM, Conceptualization, Writing—original draft, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

11. Elisabetta Menna

    1. IRCCS Humanitas, Rozzano, Italy
    2. IN-CNR, Milano, Italy

    Contribution

    EM, Conceptualization, Data curation, Formal analysis, Writing—original draft, Writing—review and editing

    Competing interests

    The authors declare that no competing interests exist.

12. Angel Barco

    Instituto de Neurociencias (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Alicante, Spain

    Contribution

    AB, Data curation, Formal analysis, Writing—original draft

    Competing interests

    The authors declare that no competing interests exist.

13. Michela Matteoli

    1. IRCCS Humanitas, Rozzano, Italy
    2. IN-CNR, Milano, Italy

    Contribution

    MM, Conceptualization, Data curation, Supervision, Funding acquisition, Writing—original draft, Project administration, Writing—review and editing

    For correspondence

    michela.matteoli@humanitasresearch.it

    Competing interests

    The authors declare that no competing interests exist.

    "This ORCID iD identifies the author of this article:" 0000-0002-3569-7843

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