scholarly journals Maternal immune activation causes age-specific changes in cytokine receptor expression in offspring throughout development

2018 ◽  
Author(s):  
Myka L. Estes ◽  
Bradford M. Elmer ◽  
Cameron C. Carter ◽  
A. Kimberley McAllister
Keyword(s):  
Immune Activation ◽  
Synapse Formation ◽  
Early Adulthood ◽  
Neuropsychiatric Disorders ◽  
Receptor Expression ◽  
Cytokine Receptor ◽  
Cytokine Receptors ◽  
Cytokine Signaling ◽  
Peak Period ◽  
Maternal Immune Activation

Maternal infection is a shared environmental risk factor for a spectrum of neuropsychiatric disorders and animal models of maternal immune activation (MIA) exhibit a range of neuropathologies and behaviors with relevance to these disorders. In particular, MIA offspring show chronic, age- and region-dependent changes in brain cytokines, a feature seen in postmortem studies of individuals with neuropsychiatric disorders. These MIA-induced alterations in brain cytokines may index biological processes underlying progression to diagnosable neuropsychiatric disorders. However, cytokines signal through specific cytokine receptors to alter cellular processes and it is the levels of those receptors that are critical for signaling. Yet, it remains unknown whether MIA alters the expression of cytokine receptors in the brains of offspring throughout postnatal development. Here, we measured the expression of 23 cytokine receptors in the frontal cortex of MIA and control offspring from birth to adulthood using qPCR. MIA offspring show dynamic oscillating alterations in cytokine receptors during sensitive periods of neural growth and synaptogenesis. Of the many cytokine receptors altered in the FC of MIA offspring, five were significantly changed at multiple ages at levels over 2-fold relative to controls (Il1r1, Ifngr1, Il10ra, Cx3cr1 and Gmcsfr), suggesting persistent dysfunction within those pathways. In addition to facilitating immune responses, these cytokine receptors play critical roles in neuronal migration and maturation, synapse formation and elimination, and microglial function. Together with previously reported changes in cytokine levels in the brains of MIA offspring, our results show a decrease in cytokine signaling during the peak period of synaptogenesis and spine formation and an increase during periods of activity-dependent developmentand early adulthood. Overall, the oscillating, age-dependent cytokine receptor alterations in the FC of MIA offspring identified here may have diagnostic and therapeutic value for neuropsychiatric disorders with a neuro-immune etiology.

Cytokines and endotoxin induce cytokine receptors in skeletal muscle

2000 ◽  
Vol 279 (1) ◽  
pp. E196-E205 ◽  
Author(s):  
Yan Zhang ◽  
Geneviève Pilon ◽  
André Marette ◽  
Vickie E. Baracos
Keyword(s):  
Skeletal Muscle ◽  
Interleukin 1 ◽  
Intraperitoneal Administration ◽  
Interferon Γ ◽  
Receptor Expression ◽  
Cytokine Receptor ◽  
Cytokine Receptors ◽  
Type I ◽  
Skeletal Muscle Function ◽  
Tnf Α

Proinflammatory cytokines are important factors in the regulation of diverse aspects of skeletal muscle function; however, the muscle cytokine receptors mediating these functions are uncharacterized. Binding kinetics (dissociation constant = 39 ± 4.7 × 10−9M, maximal binding = 3.5 ± 0.23 × 10−12mol/mg membrane protein) of muscle tumor necrosis factor (TNF) receptors were obtained. Skeletal muscle was found to express mRNAs encoding interleukin-1 type I and II receptors, interleukin-6 receptor (IL-6R), and interferon-γ receptor by RT-PCR, but these receptors were below limits of detection of ligand-binding assay (≥1 fmol binding sites/mg protein). Twenty-four hours after intraperitoneal administration of endotoxin to rats, TNF receptor type II (TNFRII) and IL-6R mRNA were increased in skeletal muscle ( P < 0.05). In cultured L6 cells, the expression of mRNA encoding TNFRII and IL-6R receptors was induced by TNF-α, and all six cytokine receptor mRNA were induced by a mixture of TNF-α, IFN-γ, and endotoxin ( P < 0.05). This suggests that the low level of cytokine receptor expression is complemented by a capacity for receptor induction, providing a clear mechanism for amplification of cytokine responses at the muscle level.

scholarly journals Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring

2020 ◽  
Vol 21 (11) ◽  
pp. 4097 ◽  
Author(s):  
Magdalena Cieślik ◽  
Magdalena Gąssowska-Dobrowolska ◽  
Henryk Jęśko ◽  
Grzegorz A. Czapski ◽  
Anna Wilkaniec ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Immune Activation ◽  
Protein Level ◽  
Behavioral Changes ◽  
Adolescent Male ◽  
Male Rat ◽  
Cytokine Signaling ◽  
Maternal Immune Activation ◽  
Rat Offspring ◽  
Synaptic Ultrastructure

Maternal immune activation (MIA), induced by infection during pregnancy, is an important risk factor for neuro-developmental disorders, such as autism. Abnormal maternal cytokine signaling may affect fetal brain development and contribute to neurobiological and behavioral changes in the offspring. Here, we examined the effect of lipopolysaccharide-induced MIA on neuro-inflammatory changes, as well as synaptic morphology and key synaptic protein level in cerebral cortex of adolescent male rat offspring. Adolescent MIA offspring showed elevated blood cytokine levels, microglial activation, increased pro-inflammatory cytokines expression and increased oxidative stress in the cerebral cortex. Moreover, pathological changes in synaptic ultrastructure of MIA offspring was detected, along with presynaptic protein deficits and down-regulation of postsynaptic scaffolding proteins. Consequently, ability to unveil MIA-induced long-term alterations in synapses structure and protein level may have consequences on postnatal behavioral changes, associated with, and predisposed to, the development of neuropsychiatric disorders.

scholarly journals Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: an integrated neuroimaging, behavioural, and transcriptional study

2020 ◽  
Author(s):  
Elisa Guma ◽  
Pedro Bordignon ◽  
Gabriel Allan Devenyi ◽  
Daniel Gallino ◽  
Chloe Anastassiadis ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Dorsal Hippocampus ◽  
Early Adulthood ◽  
Sensorimotor Gating ◽  
Cingulate Cortex ◽  
Late Gestation ◽  
Anterior Cingulate ◽  
Poly I:C ◽  
Maternal Immune Activation

Prenatal maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders. How gestational timing of MIA-exposure differentially impacts downstream development remains unclear. Here, we characterize neurodevelopmental trajectories of mice exposed to MIA induced by poly I:C either early (gestational day [GD]9) or late (GD17) in gestation using longitudinal structural magnetic resonance imaging from weaning to adulthood. Early MIA-exposure associated with accelerated brain volume increases in adolescence/early-adulthood that normalized in later adulthood, in regions including the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety, stereotypic, and sensorimotor gating behaviours observed in adolescence normalized in adulthood. In contrast, MIA-exposure in late gestation had less impact on anatomical and behavioural profiles. Using a multivariate technique to relate imaging and behavioural variables for the time of greatest alteration, i.e. adolescence/early adulthood, we demonstrate that variation in anxiety, social, and sensorimotor gating associates significantly with volume of regions including the dorsal and ventral hippocampus, and anterior cingulate cortex. Using RNA sequencing to explore the molecular underpinnings of region-specific alterations in early MIA-exposed mice in adolescence, we observed the most transcriptional changes in the dorsal hippocampus, with regulated genes enriched for fibroblast growth factor regulation, autistic behaviours, inflammatory pathways, and microRNA regulation. This indicates that MIA in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders. Our findings demonstrate the power of an integrated hypothesis- and data-driven approach in linking brain-behavioural alterations to the transcriptome to understand how MIA confers risk for major mental illness.

scholarly journals Maternal immune activation generates anxiety in offspring: A translational meta-analysis

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S268-S268
Author(s):  
Ursula Matos ◽  
Laiana Azevedo Quagliato ◽  
Antonio Egidio Nardi
Keyword(s):  
Anxiety Disorders ◽  
Immune Activation ◽  
Synapse Formation ◽  
Meta Analysis ◽  
Fetal Brain ◽  
Cochrane Library ◽  
Future Research ◽  
Maternal Immune Activation ◽  
Genetic And Environmental Factors ◽  
And Function

AimsMaternal immune activation (MIA) during pregnancy is recognized as an etiological risk factor for various psychiatric disorders, such as schizophrenia, major depressive disorder, and autism. Prenatal immune challenge may serve as a “disease primer” into an altered trajectory of fetal brain development that, in combination with other genetic and environmental factors, may ultimately result in the emergence of different psychiatric conditions. However, the association between MIA and the offspring's chances of developing anxiety disorders is less clear. To examine the effect of MIA on offspring anxiety, a systematic review and meta-analysis of the preclinical literature was conducted.MethodA systematic search of the PubMed, Web of Science, PsycINFO, and Cochrane Library electronic databases was performed using the PRISMA and WHO methodologies for systematic reviews. Studies that investigated if MIA during rodent's pregnancy could cause anxiety symptoms in offspring were included.ResultOverall, the meta-analysis showed that MIA induced anxiety behavior in offspring. The studies provide strong evidence that prenatal immune activation impacts specific molecular targets, synapse formation and function, and a disbalance in neurotransmission that could be related to the generation of offspring anxiety. Future research should further explore the role of MIA in anxiety endophenotypes.ConclusionAccording to this meta-analysis, MIA plays an important role in the pathophysiological mechanisms of anxiety disorders and provides a promising therapeutic target.

Early response to bleomycin is characterized by different cytokine and cytokine receptor profiles in lungs

2004 ◽  
Vol 287 (6) ◽  
pp. L1186-L1192 ◽  
Author(s):  
Eleonora Cavarra ◽  
Fabio Carraro ◽  
Silvia Fineschi ◽  
Antonella Naldini ◽  
Barbara Bartalesi ◽  
...  
Keyword(s):  
Rnase Protection Assay ◽  
Early Response ◽  
Receptor Expression ◽  
Cytokine Receptor ◽  
Cytokine Receptors ◽  
Mouse Strains ◽  
Ether Anesthesia ◽  
Rnase Protection ◽  
Tnf Α ◽  
Different Strains

The sensitivity to the fibrosis-inducing effect of bleomycin varies considerably from species to species, the reasons for which are unknown. The variability of the response in different strains of mice is well documented. Recent evidence indicates that the upregulated expression of cytokines and cytokine receptors may be involved. We evaluated the expression pattern of some cytokines and their receptors in C57Bl/6J bleomycin-sensitive and Balb/C bleomycin-resistant mice. Animals from both strains received, under ether anesthesia, either saline (50 μl) or bleomycin (0.1 U/50 μl) intratracheally. At various times after the treatment, the lungs were analyzed for cytokines and cytokine receptors by histochemistry and their mRNA by RNase protection assay. A significantly increased expression of TNF-α and IL-1β was observed in both strains. However, an upregulated lung expression for TNF-α and IL-1 receptors was observed in C57Bl/6J-sensitive animals only. This profile is evident from 63 h onward. In addition to TNF-α, bleomycin administration also resulted in the upregulated expression of TGF-β in the lungs of both strains at 8 h and in an enhanced expression of TGF-β receptors I and II in C57Bl/6J mice only. The upregulation of TGF-β receptor expression was preceded in this strain by an increased expression of IL-4, IL-13, and IL-13 receptor-α (at 8 h after bleomycin) and followed by an upregulation of gp130 and IL-6. The difference we observed in the cytokine receptor profile may offer an additional explanation for the different fibrogenic response of the two mouse strains to bleomycin.

scholarly journals Maternal immune activation: Implications for neuropsychiatric disorders

Science ◽  
2016 ◽  
Vol 353 (6301) ◽  
pp. 772-777 ◽  
Author(s):  
M. L. Estes ◽  
A. K. McAllister
Keyword(s):  
Immune Activation ◽  
Neuropsychiatric Disorders ◽  
Maternal Immune Activation

Study on the Membrane Hemopoietic Cytokine Receptor Expression on CD34+ Bone Marrow Cells of the Patients with Myelodysplastic Syndromes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2908-2908
Author(s):  
Zonghong Shao ◽  
Lijuan Li ◽  
Rong Fu ◽  
Huaquan Wang ◽  
Lanzhu Yue ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Bone Marrow Cells ◽  
Low Risk ◽  
Receptor Expression ◽  
Cytokine Receptor ◽  
Cytokine Receptors ◽  
Control Group ◽  
The Mean ◽  
Marrow Cells

Abstract Abstract 2908 Objectives This study was to detect if there were abnormalities of membrane hemopoietic cytokine receptor expression on CD34+ bone marrow cells in MDS. Methods 34 newly diagnosed MDS(12 in low-risk and 22 in high-risk) cases and 32 normal controls were enrolled in this study. Their CD34+CD38+ and CD34+CD38- bone marrow cells and the expressions of stem cell factor receptor(SCF-R),erythropoietin receptor (EpoR), granulocyte colony-stimulating factor receptor (G-CSFR) and thrombopoietin receptor (TpoR) on those cells were measured by flow cytometry. Results The mean percentage of CD34+ BMMNCs of MDS cases in high risk[(2.94±4.79)%)] was significantly higher than that of control group[(0.95±1.06)%](P<0.05). The mean percentages of CD34+CD38+ cells were significantly lower in low risk and high risk groups[(86.98±6.83)% and (83.57±9.86)% respectively] than that in control group [(92.41±3.43)%], thus the percentage of CD34+CD38- cells was significantly higher in either low-risk or high-risk group[(13.03±6.84)% and (16.42±9.85)% respectively]than that in control group[(7.59±3.43)%](P<0.05). In control group, the mean percentage of antigen expression of EpoR was significantly lower in CD34+CD38+ cells [(17.72±20.24) %] than that in CD34+CD38- cells [(64.65±21.02)%](P<0.01), The expressions of SCF-R,G-CSFR and TpoR on CD34+CD38- cells were not significantly different from these on CD34+CD38+ cells. The expression of EpoR on CD34+CD38+ cells of low-risk and high-risk MDS groups[(7.01±6.82)% and (7.16±9.45)% respectively] were significantly lower than that of control group[(17.72±20. 24) %] (P<0.05), The expression of G-CSFR on CD34+CD38+ cells of low-risk and high-risk MDS groups[(22.65±12.14)% and (26.50±19.65)% respectively] were significantly lower than that of control group[(45.13±23.41)%](P<0.01). The amount of EpoR on CD34+CD38-cells of low-risk and high-risk MDS groups[(40.18±20.38)% and (28.58±17.00)% respectively] were significantly lower than that of control group[(64.65±21.02)%](P<0.01), The expression of TpoR on CD34+CD38- cells of low-risk and high-risk MDS groups[(4.46±7.45)% and (3.23±4.55)% respectively] were significantly lower than that of control group[(15.33±14.95)%](P<0.01). The incidence of cytopenia of MDS cases with low expression rates of hemopoietic cytokine receptors on CD34+cells were higher than that of MDS with high expression rates of hemopoietic cytokine receptors. Conclusions There were abnormalities of differentiation and membrane hemopoietic cytokine receptors expression of CD34+ bone marrow cells in MDS, which were associated with MDS cytopenia and might be useful for MDS diagnosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Maternal obesity and developmental programming of neuropsychiatric disorders: An inflammatory hypothesis

2021 ◽  
Vol 5 ◽  
pp. 239821282110034
Author(s):  
Jonathan Davis ◽  
Erik Mire
Keyword(s):  
Fatty Acids ◽  
Immune Activation ◽  
Maternal Obesity ◽  
Epigenetic Modification ◽  
Neuropsychiatric Disorders ◽  
Intervention Strategies ◽  
Maternal Immune Activation ◽  
Cytokine Levels ◽  
Inflammatory Processes ◽  
Placental Inflammation

Maternal obesity is associated with the development of a variety of neuropsychiatric disorders; however, the mechanisms behind this association are not fully understood. Comparison between maternal immune activation and maternal obesity reveals similarities in associated impairments and maternal cytokine profile. Here, we present a summary of recent evidence describing how inflammatory processes contribute towards the development of neuropsychiatric disorders in the offspring of obese mothers. This includes discussion on how maternal cytokine levels, fatty acids and placental inflammation may interact with foetal neurodevelopment through changes to microglial behaviour and epigenetic modification. We also propose an exosome-mediated mechanism for the disruption of brain development under maternal obesity and discuss potential intervention strategies.

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