Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring

Mirabella, Filippo; Desiato, Genni; Mancinelli, Sara; Fossati, Giuseppe; Rasile, Marco; Morini, Raffaella; Markicevic, Marija; Grimm, Christina; Amegandjin, Clara A.; Termanini, Alberto; Peano, Clelia; Kunderfranco, Paolo; Cristo, Graziella Di; Zerbi, Valerio; Menna, Elisabetta; Lodato, Simona; Matteoli, Michela; Pozzi, Davide

doi:10.1016/j.immuni.2021.10.006

Cited by 74 publications

(64 citation statements)

References 180 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the factors associated with CNS disorders, it is curious that non-CNS disruptions such as allergies (Akdis, 2021 ), gastrointestinal disorders (Bresnahan et al, 2015 ), and mitochondrial dysfunctions (Giulivi et al, 2010 ) are also associated with autism. Specifically, prenatal exposure to maternal immune activation (MIA) is considered a key environmental risk factor for ASD (Han et al, 2021 ; Mirabella et al, 2021 ; Xu et al, 2021 ). Animal models for ASD conducted by prenatal exposure, including prenatal infection, valproic acid, propionic acid, poly (I:C) or lipopolysaccharides exposure, can cause ASD-like behaviors, such as specific impairments in social interaction, communication and repetitive behaviors (Ergaz et al, 2016 ; Mintál et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

Wang

et al. 2022

Front. Neuroinform.

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, characterized by marked genetic heterogeneity. In this study, two independent microarray datasets of cerebellum of ASD were integrative analyzed by NetworkAnalyst to screen candidate crucial genes. NetworkAnalyst identified two up-regulated genes, Jun proto-oncogene (JUN) and platelet derived growth factor receptor alpha (PDGFRA), as the most crucial genes in cerebellum of ASD patients. Based on KEGG pathway database, genes associated with JUN in the cerebellum highlight the pathways of Th17 cell differentiation and Th1 and Th2 cell differentiation. Genes associated with PDGFRA in the cerebellum were found enriched in pathways in EGFR tyrosine kinase inhibitor resistance and Rap1 signaling pathway. Analyzing all differentially expressed genes (DEGs) from the two datasets, Gene Set Enrichment Analysis (GSEA) brought out IL17 signaling pathway, which is related to the expression of JUN and PDGFRA. The ImmuCellAI found the elevated expression of JUN and PDGFRA correlating with increased Th17 and monocytes suggests JUN and PDGFRA may regulate Th17 cell activation and monocytes infiltrating. Mice model of maternal immune activation demonstrated that JUN and PDGFRA are up-regulated and related to the ASD-like behaviors that provide insights into the molecular mechanisms underlying the altered IL17 signaling pathway in ASD and may enable novel therapeutic strategies.

show abstract

Section: Introductionmentioning

confidence: 99%

JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

Wang

et al. 2022

Front. Neuroinform.

View full text Add to dashboard Cite

show abstract

“…Moreover, the underlying molecular mechanisms the are exerted on the developing brain and on specific cell types, remain to be fully elucidated. Evidence from animal models of MIA provides support for the involvement of altered levels of interleukins, particularly interleukin-(IL)-6, IL-1beta and IL-10 but also for the cytokines TNF-alpha, and interferon-γ (IFNγ) ( 6 , 22 – 24 ). Of these, IFNγ has been found to have increased levels in the plasma of first-episode schizophrenia patients ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

Interferon-γ exposure of human iPSC-derived neurons alters major histocompatibility complex I and synapsin protein expression

et al. 2022

View full text Add to dashboard Cite

Human epidemiological data links maternal immune activation (MIA) during gestation with increased risk for psychiatric disorders with a putative neurodevelopmental origin, including schizophrenia and autism. Animal models of MIA provide evidence for this association and suggest that inflammatory cytokines represent one critical link between maternal infection and any potential impact on offspring brain and behavior development. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. It is also unclear how specific cytokines may impact the development of specific cell types. Using a human cellular model, we recently demonstrated that acute exposure to interferon-γ (IFNγ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNγ can impact the development of immature glutamatergic neurons using an induced neuronal cellular system. We find that acute exposure to IFNγ activates a signal transducer and activator of transcription 1 (STAT1)-pathway in immature neurons, and results in significantly increased major histocompatibility complex I (MHCI) expression at the mRNA and protein level. Furthermore, acute IFNγ exposure decreased synapsin I/II protein in neurons but did not affect the expression of synaptic genes. Interestingly, complement component 4A (C4A) gene expression was significantly increased following acute IFNγ exposure. This study builds on our previous work by showing that IFNγ-mediated disruption of relevant synaptic proteins can occur at early stages of neuronal development, potentially contributing to neurodevelopmental disorder phenotypes.

show abstract

“…It is also important to consider that TNF-α and IL-17, in addition to other inflammatory mediators whose levels are commonly increased in COVID-19 patients (C-reactive protein, IL-1β, IL-2, IL-8, and interferons), may contribute to neurodevelopmental and neuropsychiatric diseases related to maternal immune activation (Jiang et al, 2018). Although the mechanisms by which cytokines affect brain development remain poorly understood, they seem to involve changes in functional brain connectivity, white matter damage, and abnormalities in neurotransmission (Jiang et al, 2018;Mirabella et al, 2021;Saunders et al, 2020). Cytokines from the periphery can also induce CNS responses in several ways, including diffusion across the disrupted BBB and induction of synthesis and release of cytokines by glial cells (Gu et al, 2021;Jiang et al, 2018).…”

Section: Current Evidence On Sars-cov-2 Vertical Transmissionmentioning

confidence: 99%

Impact of SARS-CoV-2 infection during pregnancy on postnatal brain development: The potential role of glial cells

Bobermin¹,

Medeiros²,

Weber³

et al. 2022

Biocell

View full text Add to dashboard Cite

Glial cells are crucial for maintaining central nervous system (CNS) homeostasis. They actively participate in immune responses, as well as form functional barriers, such as blood-brain barrier (BBB), which restrict the entry of pathogens and inflammatory mediators into the CNS. In general, viral infections during the gestational period can alter the embryonic and fetal environment, and the related inflammatory response may affect neurodevelopment and lead to behavioral dysfunction during later stage of life, as highlighted by our group for Zika virus infection. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces a cytokine storm and, during pregnancy, may be related to a more severe form of the coronavirus disease-19 (COVID-19) and also to higher preterm birth rates. SARS-CoV-2 can also affect the CNS by inducing neurochemical remodeling in neural cells, which can compromise neuronal plasticity and synaptic function. However, the impact of SARS-CoV-2 infection during pregnancy on postnatal CNS, including brain development during childhood and adulthood, remains undetermined. Our group has recently highlighted the impact of COVID-19 on the expression of molecular markers associated with neuropsychiatric disorders, which are strongly related to the inflammatory response. Thus, based on these relationships, we discussed the impact of SARS-CoV-2 infection either during pregnancy or in critical periods of neurodevelopment as a risk factor for neurological consequences in the offspring later in life, focusing on the potential role of glial cells. Thus, it is important to consider future and long-term public health concerns associated with SARS-CoV-2 infection during pregnancy.

show abstract

Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring

Cited by 74 publications

References 180 publications

JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

JUN and PDGFRA as Crucial Candidate Genes for Childhood Autism Spectrum Disorder

Interferon-γ exposure of human iPSC-derived neurons alters major histocompatibility complex I and synapsin protein expression

Impact of SARS-CoV-2 infection during pregnancy on postnatal brain development: The potential role of glial cells

Contact Info

Product

Resources

About