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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 -
Molecular Immunology Aug 2021Reticuloendothelial virus (REV) is widely found in many domestic poultry areas and results in severe immunosuppression of infected chickens. This increases the...
Reticuloendothelial virus (REV) is widely found in many domestic poultry areas and results in severe immunosuppression of infected chickens. This increases the susceptibility to other pathogens, which causes economic losses to the poultry industry. The aim of our study was to determine whether polyinosinic-polycytidylic acid [Poly (I: C)] treatment could inhibit REV replication in chicken macrophage-like cell line, HD11. We found that Poly (I: C) treatment could markedly inhibit REV replication in HD11 from 24 to 48 h post infection (hpi). Additionally, Poly (I: C) treatment could switch HD11 from an inactive type into M1-like polarization from 24 to 48 hpi. Furthermore, Poly (I: C) treatment promoted interferon-β secretion from HD11 post REV infection. Moreover, Toll-like receptor-3 (TLR-3) mRNA and protein levels in HD11 treated with Poly (I: C) were markedly increased compared to those of HD11 not treated with Poly (I: C). The above results suggested that Poly (I: C) treatment switches HD11 into M1-like polarization to secret more interferon-β and activate TLR-3 signaling, which contributes to block REV replication. Our findings provide a theoretical reference for further studying the underlying pathogenic mechanism of REV and Poly (I: C) as a potential therapeutic intervention against REV infection.
Topics: Animals; Antiviral Agents; Cell Line; Chickens; Interferon Inducers; Interferon-beta; Macrophages; Poly I-C; Reticuloendotheliosis Viruses, Avian; Retroviridae Infections; Signal Transduction; Toll-Like Receptor 3; Tumor Virus Infections; Virus Replication
PubMed: 34098343
DOI: 10.1016/j.molimm.2021.05.013 -
CNS Neuroscience & Therapeutics Aug 2022Toll-like receptor (TLR) agonist polyinosinic-polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Toll-like receptor (TLR) agonist polyinosinic-polycytidylic acid (poly I:C) exerts neuroprotective effects against cerebral ischemia (CI), but concrete evidence supporting its exact mechanism of action is unclear.
METHODS
We evaluated the neuroprotective role of poly I:C by assessing CI indicators such as brain infarct volume (BIV), neurological deficit score (N.S.), and signaling pathway proteins. Moreover, we performed a narrative review to illustrate the mechanism of action of TLRs and their role in CI. Our search identified 164 articles and 10 met the inclusion criterion.
RESULTS
Poly I:C reduces BIV and N.S. (p = 0.00 and p = 0.03). Interestingly, both pre- and post-conditioning decrease BIV (preC p = 0.04 and postC p = 0.00) and N.S. (preC p = 0.03 and postC p = 0.00). Furthermore, poly I:C upregulates TLR3 [SMD = 0.64; CIs (0.56, 0.72); p = 0.00], downregulates nuclear factor-κB (NF-κB) [SMD = -1.78; CIs (-2.67, -0.88); p = 0.0)], and tumor necrosis factor alpha (TNF-α) [SMD = -16.83; CIs (-22.63, -11.02); p = 0.00].
CONCLUSION
We showed that poly I:C is neuroprotective and acts via the TLR3/NF-κB/TNF-α pathway. Our review indicated that suppressing TLR 2/4 may illicit neuroprotection against CI. Further research on simultaneous activation of TLR3 with poly I:C and suppression of TLR 2/4 might open new vistas for the development of therapeutics against CI.
Topics: Animals; Brain Infarction; Brain Injuries; Brain Ischemia; Cerebral Infarction; NF-kappa B; Neuroprotective Agents; Poly I-C; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptor 3; Tumor Necrosis Factor-alpha
PubMed: 35510663
DOI: 10.1111/cns.13851 -
Scientific Reports Feb 2023A wide body of evidence suggests a relationship between maternal immune activation (MIA) and neurodevelopmental disorders such as autism spectrum disorder (ASD). Since...
A wide body of evidence suggests a relationship between maternal immune activation (MIA) and neurodevelopmental disorders such as autism spectrum disorder (ASD). Since social and communicative deficits are included in the first diagnostic criterion of ASD, we aimed to characterize socio-communicative behaviors in the MIA model based on prenatal exposure to poly(I:C). Our previous studies demonstrated impaired socio-communicative functioning in poly(I:C)-exposed adolescent rats. Therefore, the current study sought to clarify whether these changes would persist beyond adolescence. For this purpose, we analyzed behavior during the social interaction test and recorded ultrasonic vocalizations (USVs) accompanying interactions between adult poly(I:C) rats. The results demonstrated that the altered pattern of social behavior in poly(I:C) males was accompanied by the changes in acoustic parameters of emitted USVs. Poly(I:C) males also demonstrated an impaired olfactory preference for social stimuli. While poly(I:C) females did not differ from controls in socio-positive behaviors, they displayed aggression during the social encounter and were more reactive to somatosensory stimulation. Furthermore, the locomotor pattern of poly(I:C) animals were characterized by repetitive behaviors. Finally, poly(I:C) reduced parvalbumin and GAD67 expression in the cerebellum. The results showed that prenatal poly(I:C) exposure altered the pattern of socio-communicative behaviors of adult rats in a sex-specific manner.
Topics: Pregnancy; Male; Humans; Female; Rats; Animals; Behavior, Animal; Autism Spectrum Disorder; Disease Models, Animal; Prenatal Exposure Delayed Effects; Social Behavior; Poly I-C
PubMed: 36732579
DOI: 10.1038/s41598-023-28919-z -
Viruses May 2023Immunopathology in hepatitis B virus (HBV) infection is driven by innate and adaptive immunity. Whether the hepatitis B surface antigen (HBsAg) affects hepatic antiviral...
Immunopathology in hepatitis B virus (HBV) infection is driven by innate and adaptive immunity. Whether the hepatitis B surface antigen (HBsAg) affects hepatic antiviral signalling was investigated in HBV-transgenic mouse models that either accumulate (Alb/HBs, Tg[Alb1HBV]Bri44), lack (Tg1.4HBV-s-mut3) or secrete (Tg1.4HBV-s-rec (F1, Tg1.4HBV-s-mut × Alb/HBs) the HBsAg. Herein, the responsiveness of TLR3 and RIG-I in primary parenchymal and non-parenchymal liver cells was determined in vitro and in vivo. Cell type-specific and mouse strain-dependent interferon, cytokine and chemokine expression were observed by LEGENDplex™ and validated by quantitative PCR. In vitro, the hepatocytes, liver sinusoidal endothelial cells and Kupffer cells of Tg1.4HBV-s-rec mice showed poly(I:C) susceptibilities similar to the wild-type controls, while in the remaining leucocyte fraction the interferon, cytokine and chemokine induction was reduced. On the contrary, poly(I:C)-injected 1.4TgHBV-s-rec mice showed suppressed interferon, cytokine and chemokine levels in hepatocytes but increased levels in the leucocyte fraction. Thus, we concluded that liver cells of Tg1.4HBV-s-rec mice, which produce HBV particles and release the HBsAg, responded to exogenous TLR3/RIG-I stimuli in vitro but exhibited a tolerogenic environment in vivo.
Topics: Mice; Animals; Hepatitis B virus; Mice, Transgenic; Hepatitis B Surface Antigens; Toll-Like Receptor 3; Endothelial Cells; Hepatocytes; Liver; Interferons; Cytokines; Hepatitis B; Poly I-C
PubMed: 37243287
DOI: 10.3390/v15051203 -
Neuroscience Letters Sep 2023Maternal immune activation is one of the environmental risk factors for offspring to develop psychiatric disorders. A synthetic viral mimetic immunogen,...
Maternal immune activation is one of the environmental risk factors for offspring to develop psychiatric disorders. A synthetic viral mimetic immunogen, polyinosinic-polycytidylic acid (poly(I:C)), is used to induce maternal immune activation in animal models of psychiatric disorders. In the mouse poly(I:C) model, the existence of segment filamentous bacteria (SFB) in the maternal intestine has been reported to be important for the induction of ASD-related behavioral alterations as well as atypical cortical development called cortical patches. This study aimed to elucidate the effect of a single poly(I:C) injection during embryonic day (E) 9 to E16 on offspring's behavior in the ensured absence of maternal SFB by vancomycin drinking in C57BL/6N mice. The cortical patches were not found at either injection timings with poly(I:C) or PBS vehicle, tested in male or female offspring at postnatal day 0 or 1. Prepulse inhibition was decreased in male adult offspring most strongly at poly(I:C) injection timings later than E11, whereas a modest but significant decrease was observed in female offspring with an injection during E12 to E15. The decrease in social interaction was observed in female offspring most conspicuously at injection timings later than E11, whereas a significant decrease was observed in male offspring with an injection during E12 to E15. In conclusion, this study indicated that behavioral alterations could be induced without maternal SFB. The effect on behavior was substantially different between males and females.
Topics: Humans; Mice; Adult; Animals; Female; Male; Mice, Inbred C57BL; Poly I-C; Disease Models, Animal; Bacteria; Cytoskeleton
PubMed: 37652351
DOI: 10.1016/j.neulet.2023.137467 -
Journal of Neuroinflammation Sep 2021The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is...
BACKGROUND
The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences in neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation.
METHODS
Here, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6N mice.
RESULTS
We observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1α, IL-1β, IL-4, IL-6, TNFα, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNα and IFNγ in response to poly I:C, whereas both males and females exhibited elevations of IFNβ, demonstrating a specific sex difference in the anti-viral response in the hippocampus.
CONCLUSION
Our data suggest that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on cognition. Together, these findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders.
Topics: Animals; Chemokines; Cytokines; Female; Hippocampus; Male; Mice; Poly I-C; Sex Characteristics
PubMed: 34488804
DOI: 10.1186/s12974-021-02235-7 -
Behavioural Brain Research Jan 2022Avoidance of sick individuals is vital to the preservation of one's health and preventing transmission of communicable diseases. To do this successfully, one must...
Avoidance of sick individuals is vital to the preservation of one's health and preventing transmission of communicable diseases. To do this successfully, one must identify social cues for sickness, which include sickness behaviors and chemosignals, and use this information to orchestrate social interactions. While many social species are highly capable with this process, the neural mechanisms that provide for social responses to sick individuals are only partially understood. To this end, we used a task in which experimental rats were allowed to investigate two conspecifics, one healthy and one sick. To imitate sickness, one conspecific received the viral mimic Polyinosinic:polycytidylic acid (Poly I:C) and the other saline. In a 5-minute social preference test, experimental male and female adult rats avoided Poly I:C treated adult conspecifics but did not adjust social interaction in response to Poly I:C treated juvenile conspecifics. Seeking a neural locus of this behavior, we inhibited the insular cortex, a region necessary for social behaviors directed toward conspecifics in distress. Insular cortex inactivation via administration of the GABA agonist muscimol to experimental rats prior to social preference tests eliminated the preference to avoid sick adult conspecifics. These results suggest that some aspect of conspecific illness may be encoded in the insular cortex which is anatomically positioned to coordinate a situationally appropriate social response.
Topics: Animals; Antiviral Agents; Avoidance Learning; Behavior, Animal; Female; GABA-A Receptor Agonists; Illness Behavior; Insular Cortex; Male; Muscimol; Odorants; Poly I-C; Rats; Social Interaction
PubMed: 34425184
DOI: 10.1016/j.bbr.2021.113541 -
Oncoimmunology Jun 2020Toll-like receptor 3 (TLR3) is a pattern recognition receptor that senses exogenous (viral) as well as endogenous (mammalian) double-stranded RNA in endosomes. On... (Review)
Review
UNLABELLED
Toll-like receptor 3 (TLR3) is a pattern recognition receptor that senses exogenous (viral) as well as endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates a signal transduction pathway that culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter is essential not only for innate immune responses to infection but also for the initiation of antigen-specific immunity against viruses and malignant cells. These aspects of TLR3 biology have supported the development of various agonists for use as stand-alone agents or combined with other therapeutic modalities in cancer patients. Here, we review recent preclinical and clinical advances in the development of TLR3 agonists for oncological disorders.
ABBREVIATIONS
cDC, conventional dendritic cell; CMT, cytokine modulating treatment; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocyte; DC, dendritic cell; dsRNA, double-stranded RNA; FLT3LG, fms-related receptor tyrosine kinase 3 ligand; HNSCC, head and neck squamous cell carcinoma; IFN, interferon; IL, interleukin; ISV, vaccine; MUC1, mucin 1, cell surface associated; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; polyA:U, polyadenylic:polyuridylic acid; polyI:C, polyriboinosinic:polyribocytidylic acid; TLR, Toll-like receptor.
Topics: Animals; Dendritic Cells; Humans; Neoplasms; Poly I-C; T-Lymphocytes, Cytotoxic; Toll-Like Receptor 3
PubMed: 32934877
DOI: 10.1080/2162402X.2020.1771143 -
Frontiers in Immunology 2022Leishmaniasis is a neglected tropical disease (NTD) caused by parasites belonging to the genus for which there is no vaccine available for human use. Thus, the aims of...
Leishmaniasis is a neglected tropical disease (NTD) caused by parasites belonging to the genus for which there is no vaccine available for human use. Thus, the aims of this study are to evaluate the immunoprotective effect of a first-generation vaccine against and to identify its immunodominant antigens. BALB/c mice were inoculated with phosphate buffer sodium (PBS), total antigens (TLAs), or TLA with Poly (I:C) and Montanide ISA 763. The humoral and cellular immune response was evaluated before infection. IgG, IgG1, and IgG2a were measured on serum, and IFN-γ, IL-4, and IL-10 cytokines as well as cell proliferation were measured on a splenocyte culture from vaccinated mice. Immunized mice were challenged with 10 infective parasites of on the footpad. After infection, the protection provided by the vaccine was analyzed by measuring lesion size, splenic index, and parasite load on the footpad and spleen. To identify immunodominant antigens, total proteins of were separated on 2D electrophoresis gel and transferred to a membrane that was incubated with serum from immunoprotected mice. The antigens recognized by the serum were analyzed through a mass spectrometric assay (LC-MS/MS-IT-TOF) to identify their protein sequence, which was subjected to bioinformatic analysis. The first-generation vaccine induced higher levels of antibodies, cytokines, and cell proliferation than the controls after the second dose. Mice vaccinated with TLA + Poly (I:C) + Montanide ISA 763 showed less footpad swelling, a lower splenic index, and a lower parasite load than the control groups (PBS and TLA). Four immunodominant proteins were identified by mass spectrometry: cytosolic tryparedoxin peroxidase, an uncharacterized protein, a kinetoplast-associated protein-like protein, and a putative heat-shock protein DNAJ. The identified proteins showed high levels of conserved sequence among species belonging to the genus and the Trypanosomatidae family. These proteins also proved to be phylogenetically divergent to human and canine proteins. TLA + Poly (I:C) + Montanide ISA 763 could be used as a first-generation vaccine against leishmaniasis. The four proteins identified from the whole-protein vaccine could be good antigen candidates to develop a new-generation vaccine against leishmaniasis.
Topics: Animals; Chromatography, Liquid; Cytokines; Dogs; Immunodominant Epitopes; Leishmania; Leishmaniasis, Cutaneous; Mice; Mineral Oil; Poly I-C; Tandem Mass Spectrometry; Vaccines
PubMed: 35634280
DOI: 10.3389/fimmu.2022.825007