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Brain, Behavior, and Immunity Jul 2021Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings. However, the mechanisms underlying its success are not understood....
Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings. However, the mechanisms underlying its success are not understood. Incorporating components of EE protocols into our animal models allows for the exploration of these mechanisms and their role in mitigation. Using a mouse model of maternal immune activation (MIA), the present study explored disruptions in social behavior and associated hypothalamic pituitary adrenal (HPA) axis functioning, and whether a supportive environment could prevent these effects. We show that prenatal immune activation of toll-like receptor 3, by the viral mimetic polyinosinic-polycytidylic acid (poly(I:C)), led to disrupted maternal care in that dams built poorer quality nests, an effect corrected by EE housing. Standard housed male and female MIA mice engaged in higher rates of repetitive rearing and had lower levels of social interaction, alongside sex-specific expression of several ventral hippocampal neural stress markers. Moreover, MIA males had delayed recovery of plasma corticosterone in response to a novel social encounter. Enrichment housing, likely mediated by improved maternal care, protected against these MIA-induced effects. We also evaluated c-Fos immunoreactivity associated with the novel social experience and found MIA to decrease neural activation in the dentate gyrus. Activation in the hypothalamus was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. These data demonstrate that augmentation of the environment supports parental care and offspring safety/security, which can offset effects of early health adversity by buffering HPA axis dysregulation. Our findings provide further evidence for the viability of EE interventions in maternal and pediatric settings.
Topics: Animals; Child; Female; Hippocampus; Humans; Hypothalamo-Hypophyseal System; Male; Pituitary-Adrenal System; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Social Behavior
PubMed: 33766701
DOI: 10.1016/j.bbi.2021.03.018 -
American Journal of Reproductive... Jun 2019Maternal immune activation (MIA) during pregnancy is associated with increased chances of neurodevelopmental disorders including schizophrenia and autism spectrum...
PROBLEM
Maternal immune activation (MIA) during pregnancy is associated with increased chances of neurodevelopmental disorders including schizophrenia and autism spectrum disorder (ASD). However, the exact mechanism through which MIA contributes to altered neurodevelopment is unknown. Due to the important role that amino acids play in neurodevelopment, altered amino acid transport could play a role in neurodevelopmental disorders. Indeed, altered plasma concentrations of multiple amino acids have been reported in individuals with ASD or schizophrenia. Therefore, our objective was to determine whether virally mediated MIA induces changes in amino acid transporters in the placenta and fetal brain.
METHOD OF STUDY
Pregnant rats were administered poly(I:C) on gestational day 14, and placental and fetal tissues were collected 6, 24, and 48 hours later. Amino acid transporter expression was measured in the placenta and fetal brain using qPCR, Western blotting, and Simple Western. Free amino acid concentrations in the fetal brain were quantified using HPLC.
RESULTS
Poly(I:C) increased mRNA expression of several amino acid transporters in the placenta and fetal brain over these timepoints. Conversely, poly(I:C) imposed significant decreases in the protein expression of ASCT1 and EAAT2 in placenta and expression of SNAT5, EAAT1, and GLYT1 in fetal brain. Functional consequences of altered transporter expression were demonstrated through widespread changes in the concentrations of free amino acids in the fetal brains.
CONCLUSION
Together, these results represent novel findings with the poly(I:C) MIA model and contribute to the understanding of how MIA during pregnancy potentially leads to neurodevelopmental disorders.
Topics: Amino Acid Transport Systems; Amino Acids; Animals; Brain; Disease Models, Animal; Female; Immunologic Factors; Interleukin-6; Male; Placenta; Poly I-C; Pregnancy; Rats, Sprague-Dawley
PubMed: 30924965
DOI: 10.1111/aji.13115 -
Pancreatology : Official Journal of the... Nov 2023IgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8 T cells have only received brief mention, and have yet...
BACKGROUND
IgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8 T cells have only received brief mention, and have yet to be completely studied. The study aimed to investigate the expression of signaling lymphocytic activation molecule family 7 (SLAMF7) on CD8 T cells and the features of SLAMF7CD8 T cells in MRL/Mp mice with AIP.
METHODS
A murine model of AIP was established by intraperitoneal injection with polyinosinic:polycytidylic acid (poly I:C) for 8 weeks. Dexamethasone treatment was daily administrated for the last 2 weeks during a 6-week course of poly I:C. SLAMF7 expression on CD8 T cells in the spleen and pancreas was detected by flow cytometry. Granzyme B (GZMB) and cytokines including IFN-γ, TNF-α, and IL-2, were monitored in an in vitro T cell activation assay. Dexamethasone suppression assays were performed to downregulate SLAMF7 expression on T cells upon T cell receptor stimulation.
RESULTS
AIP in MRL/Mp mice was induced by repeated intraperitoneal administration of poly I:C and CD8 T cells were increased in the inflamed pancreas. SLAMF7CD8 T cells were elevated in the spleen and pancreas of AIP mice. SLAMF7CD8 T subsets produced more GZMB, IFN-γ, TNF-α and IL-2 than SLAMF7CD8 T subsets. Dexamethasone treatment ameliorated pancreatic inflammatory and fibrosis of AIP. Dexamethasone could downregulate SLAMF7CD8 T cells and reduce GZMB, IFN-γ and TNF-α levels both in vitro and in vivo.
CONCLUSIONS
Increased SLAMF7CD8 T cells exhibit enhanced cytotoxicity and cytokines secretion capacity, which may be involved in the pathogenesis of AIP.
Topics: Mice; Animals; Autoimmune Pancreatitis; CD8-Positive T-Lymphocytes; Interleukin-2; Tumor Necrosis Factor-alpha; Autoimmune Diseases; Poly I-C; Dexamethasone; Signaling Lymphocytic Activation Molecule Family
PubMed: 37661465
DOI: 10.1016/j.pan.2023.08.005 -
Neuroscience and Biobehavioral Reviews Jun 2020Maternal immune activation (MIA) in response to a viral infection during early and mid-gestation has been linked through various epidemiological studies to a higher risk... (Review)
Review
Maternal immune activation (MIA) in response to a viral infection during early and mid-gestation has been linked through various epidemiological studies to a higher risk for the child to develop autism or schizophrenia-related symptoms.. This has led to the establishment of the pathogen-free poly I:C-induced MIA animal model for neurodevelopmental disorders, which shows relatively high construct and face validity. Depending on the experimental variables, particularly the timing of poly I:C administration, different behavioural and molecular phenotypes have been described that relate to specific symptoms of neurodevelopmental disorders such as autism spectrum disorder and/or schizophrenia. We here review and summarize epidemiological evidence for the effects of maternal infection and immune activation, as well as major findings in different poly I:C MIA models with a focus on poly I:C exposure timing, behavioural and molecular changes in the offspring, and characteristics of the model that relate it to autism spectrum disorder and schizophrenia.
Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Child; Disease Models, Animal; Female; Humans; Neurodevelopmental Disorders; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects; Schizophrenia
PubMed: 32320814
DOI: 10.1016/j.neubiorev.2020.04.012 -
MBio Mar 2020Viral diseases cause significant losses in aquaculture. Prophylactic measures, such as immune priming, are promising control strategies. Treatment of the Pacific oyster...
Viral diseases cause significant losses in aquaculture. Prophylactic measures, such as immune priming, are promising control strategies. Treatment of the Pacific oyster () with the double-stranded RNA analog poly(I·C) confers long-term protection against infection with ostreid herpesvirus 1, the causative agent of Pacific oyster mortality syndrome. In a recent article in , Lafont and coauthors (M. Lafont, A. Vergnes, J. Vidal-Dupiol, J. de Lorgeril, et al., mBio 11:e02777-19, 2020, https://doi.org/10.1128/mBio.02777-19) characterized the transcriptome of oysters treated with poly(I·C). This immune stimulator induced genes related to the interferon and apoptosis pathways. This response overlaps the response to viral infection, and high expression levels of potential effector genes are maintained for up to 4 months. This work opens the door to characterization of the phenomena of immune priming in a poorly studied invertebrate model. It also highlights the importance of interferon-like responses for invertebrate antiviral immunity.
Topics: Animals; Antiviral Agents; Crassostrea; Poly I-C; RNA, Double-Stranded
PubMed: 32209685
DOI: 10.1128/mBio.00407-20 -
Scientific Reports Jun 2022Limited information is available about the effect of mid-pregnancy viral infections on the placental expression of efflux transporters and offspring behavior. We...
Limited information is available about the effect of mid-pregnancy viral infections on the placental expression of efflux transporters and offspring behavior. We hypothesized that maternal exposure to polyinosinic-polycytidylic acid [poly(I:C)], a synthetic double-stranded RNA viral mimic, would impair placental cell turnover, the expression of selected ABC transporters and adult offspring behavior. C57BL/6 mice were administered poly(I:C) (10 mg/Kg;ip) or vehicle at gestational day (GD) 13.5 (mid-pregnancy). Dams were euthanized for blood collection 4 h after injection, fetal and placental collection at GD18.5 or allowed to deliver spontaneously at term. At GD 13.5, poly(I:C) induced an acute pro-inflammatory response characterized by an increase in maternal plasma levels of IL-6, CXCL-1 and CCL-2/MCP-1. At GD 18.5, poly(I:C) decreased cell proliferation/death in the labyrinthine and increased cell death in the junctional zones, characterizing a disruption of placental cell turnover. Abca1 and Abcg1 immunolabelling was decreased in the labyrinthine zone, whereas Abca1, Abcg1 and breast cancer resistance transporter (Bcrp) expression increased in the junctional zone. Moreover, adult offspring showed motor and cognitive impairments in the Rotarod and T-water maze tests. These results indicate that viral infection during mid-pregnancy may disrupt relevant placental efflux transporters, as well as placental cell turnover and offspring behavior in adult life.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Animals; Cognitive Dysfunction; Female; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Neoplasm Proteins; Placenta; Poly I-C; Pregnancy
PubMed: 35715474
DOI: 10.1038/s41598-022-14248-0 -
International Immunology May 2020Bee venom (BV) induces skin inflammation, characterized by erythema, blisters, edemas, pain and itching. Although BV has been found to have an inhibitory effect on...
Bee venom (BV) induces skin inflammation, characterized by erythema, blisters, edemas, pain and itching. Although BV has been found to have an inhibitory effect on toll-like receptors (TLRs), we here show that BV enhances keratinocyte responses to polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3. Our results revealed that the enhanced TLR activity was primarily induced by secretory phospholipase A2 (sPLA2), a component of BV (BV-sPLA2). PLA2 mediates the hydrolysis of membrane phospholipids into lysophospholipids and free fatty acids. We demonstrated that BV-sPLA2 increased the intracellular uptake of poly(I:C), phosphorylation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs), and poly(I:C)-mediated interleukin 8 production in human keratinocytes. We further showed that the enzymatic activity of BV-sPLA2 was essential for the increased uptake of poly(I:C). These findings suggest that BV-sPLA2 may induce a modification of the cell membrane structure, leading to enhanced poly(I:C) uptake in keratinocytes. BV-sPLA2 might be able to promote wound healing by enhancing TLR3 responses.
Topics: Animals; Bee Venoms; Bees; Cells, Cultured; Humans; Interleukin-8; Keratinocytes; Phospholipases A2; Poly I-C; Toll-Like Receptors
PubMed: 31957789
DOI: 10.1093/intimm/dxaa005 -
Pharmacological Research Nov 2015The intestinal barrier function depends on an adequate response to pathogens by the epithelium. Toll-like receptor 3 (TLR-3) recognizes double-stranded RNA, a...
The intestinal barrier function depends on an adequate response to pathogens by the epithelium. Toll-like receptor 3 (TLR-3) recognizes double-stranded RNA, a virus-associated molecular pattern. Activation of TLR-3 with Poly(I:C), a synthetic agonist, modulates tissue repair and permeability in other epithelia; however, the effects of local luminal TLR-3 agonists on gut barrier function are unknown. The aim of this investigation was to evaluate short-term effects of Poly(I:C) on rat ileal and colonic permeability ex vivo. We also studied the acute effects of intrarectal administration of Poly(I:C) on colonic barrier function. Ileum tissues displayed decreased transepithelial electrical resistance (TEER) 1h after incubation with 200μg/mL Poly(I:C); however, the mucosa-to-serosa transit of macromolecules (4.4 and 40kDa dextrans - TD4.4 and FD40, respectively) remained unchanged. Conversely, colon tissue preparations stimulated with 200μg/mL Poly(I:C) showed a decreased thinning of the mucosal layer after 2h and a decreased transit of FD40 after 3h, in comparison to controls. There was no change in colonic TEER after 3h of treatment. In addition, colon tissue taken from rats 6h after an intrarectal administration of 100μg Poly(I:C) also showed decreased permeability to FD40 in the everted gut sac assay at 3h post-extraction. Tissue morphology remained unchanged. Our results suggest that an acute exposure to Poly(I:C) reduces colon permeability to macromolecules but increases ileum permeability to electrolytes/small molecules ex vivo. Although the mechanism associated to these effects needs further investigation, to our knowledge this is the first report of a direct effect of a TLR-3 ligand in intestinal barrier function and may be of significance to understand region-specific interactions between gut mucosa and microbiota.
Topics: Animals; Colon; Gastrointestinal Microbiome; Ileum; Intestinal Mucosa; Male; Permeability; Poly I-C; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 3
PubMed: 26145280
DOI: 10.1016/j.phrs.2015.06.016 -
Veterinary Immunology and... May 2024Equine influenza is a contagious respiratory disease caused by H3N8 type A influenza virus. Vaccination against equine influenza is conducted regularly; however,...
Equine influenza is a contagious respiratory disease caused by H3N8 type A influenza virus. Vaccination against equine influenza is conducted regularly; however, infection still occurs globally because of the short immunity duration and suboptimal efficacy of current vaccines. Hence the objective of this study was to investigate whether an adjuvant combination can improve immune responses to equine influenza virus (EIV) vaccines. Seventy-two mice were immunized with an EIV vaccine only or with monophosphoryl lipid A (MPL), polyinosinic-polycytidylic acid (Poly I:C), or MPL + Poly I:C. Prime immunization was followed by boost immunization after 2 weeks. Mice were euthanized at 4, 8, and 32 weeks post-prime immunization, respectively. Sera were collected to determine humoral response. Bone marrow, spleen, and lung samples were harvested to determine memory cell responses, antigen-specific T-cell proliferation, and lung viral titers. MPL + Poly I:C resulted in the highest IgG, IgG1, and IgG2a antibodies and hemagglutination inhibition titers among the groups and sustained their levels until 32 weeks post-prime immunization. The combination enhanced memory B cell responses in the bone marrow and spleen. At 8 weeks post-prime immunization, the combination induced higher CD8+ central memory T cell frequencies in the lungs and CD8+ central memory T cells in the spleen. In addition, the combination group exhibited enhanced antigen-specific T cell proliferation, except for CD4+ T cells in the lungs. Our results demonstrated improved immune responses when using MPL + Poly I:C in EIV vaccines by inducing enhanced humoral responses, memory cell responses, and antigen-specific T cell proliferation.
Topics: Animals; Influenza Vaccines; Poly I-C; Lipid A; Mice; Orthomyxoviridae Infections; Adjuvants, Immunologic; Female; Influenza A Virus, H3N8 Subtype; Antibodies, Viral; Horses; Horse Diseases; Immunoglobulin G; Immunologic Memory
PubMed: 38522410
DOI: 10.1016/j.vetimm.2024.110743 -
Immunologic Research Aug 2021Toll-like receptors 3 (TLR3) have been broadly studied among all TLRs over the last few decades together with its agonists due to their contribution to cancer... (Comparative Study)
Comparative Study Review
Toll-like receptors 3 (TLR3) have been broadly studied among all TLRs over the last few decades together with its agonists due to their contribution to cancer regression. These agonists undeniably have some shared characteristics such as mimicking dsRNA but pathways through which they exhibit antitumor properties are relatively diverse. In this review, three widely studied agonists RGC100, ARNAX, and poly-IC are discussed along with their structural and physiochemical differences including the signaling cascades through which they exert their actions. Comparison has been made to identify the finest agonist with maximum effectivity and the least side effect profile.
Topics: Adjuvants, Immunologic; Animals; Humans; Poly I-C; RNA; Toll-Like Receptor 3
PubMed: 34145551
DOI: 10.1007/s12026-021-09203-6