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International Journal of Pharmaceutics Aug 2018In this study, we aimed to investigate the immunogenicity of cationic liposomes loaded with diphtheria toxoid (DT) and poly(I:C) after hollow microneedle-mediated...
In this study, we aimed to investigate the immunogenicity of cationic liposomes loaded with diphtheria toxoid (DT) and poly(I:C) after hollow microneedle-mediated intradermal vaccination in mice. The following liposomal formulations were studied: DT loaded liposomes, a mixture of free DT and poly(I:C)-loaded liposomes, a mixture of DT-loaded liposomes and free poly(I:C), and liposomal formulations with DT and poly(I:C) either individually or co-encapsulated in the liposomes. Reference groups were DT solution adjuvanted with or without poly(I:C) (DT/poly(I:C)). The liposomal formulations were characterized in terms of particle size, zeta potential, loading and release of DT and poly(I:C). After intradermal injection of BALB/c mice with the formulations through a hollow microneedle, the immunogenicity was assessed by DT-specific ELISAs. All formulations induced similar total IgG and IgG1 titers. However, all the liposomal groups containing both DT and poly(I:C) showed enhanced IgG2a titers compared to DT/poly(I:C) solution, indicating that the immune response was skewed towards a Th1 direction. This enhancement was similar for all liposomal groups that contain both DT and poly(I:C) in the formulations. Our results reveal that a mixture of DT encapsulated liposomes and poly(I:C) encapsulated liposomes have a similar effect on the antibody responses as DT and poly(I:C) co-encapsulated liposomes. These findings may have implications for future design of liposomal vaccine delivery systems.
Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Cations; Diphtheria Toxoid; Drug Delivery Systems; Drug Liberation; Enzyme-Linked Immunosorbent Assay; Female; Immunoglobulin G; Injections, Intradermal; Liposomes; Mice; Mice, Inbred BALB C; Needles; Particle Size; Poly I-C; Vaccination
PubMed: 29870743
DOI: 10.1016/j.ijpharm.2018.06.001 -
Tissue Engineering and Regenerative... Dec 2022In this study, we have investigated whether human fetal cartilage progenitor cells (hFCPCs) have anti-inflammatory activity and can alleviate osteoarthritis (OA)...
BACKGROUND
In this study, we have investigated whether human fetal cartilage progenitor cells (hFCPCs) have anti-inflammatory activity and can alleviate osteoarthritis (OA) phenotypes in vitro.
METHODS
hFCPCs were stimulated with various cytokines and their combinations and expression of paracrine factors was examined to find an optimal priming factor. Human chondrocytes or SW982 synoviocytes were treated with interleukin-1β (IL-1β) to produce OA phenotype, and co-cultured with polyinosinic-polycytidylic acid (poly(I-C))-primed hFCPCs to address their anti-inflammatory effect by measuring the expression of OA-related genes. The effect of poly(I-C) on the surface marker expression and differentiation of hFCPCs into 3 mesodermal lineages was also examined.
RESULTS
Among the priming factors tested, poly(I-C) (1 µg/mL) most significantly induced the expression of paracrine factors such as indoleamine 2,3-dioxygenase, histocompatibility antigen, class I, G, tumor necrosis factor- stimulated gene-6, leukemia inhibitory factor, transforming growth factor-β1 and hepatocyte growth factor from hFCPCs. In the OA model in vitro, co-treatment of poly(I-C)-primed hFCPCs significantly alleviated IL-1β-induced expression of inflammatory factors such as IL-6, monocyte chemoattractant protein-1 and IL-1β, and matrix metalloproteinases in SW982, while it increased the expression of cartilage extracellular matrix such as aggrecan and collagen type II in human chondrocytes. We also found that treatment of poly(I-C) did not cause significant changes in the surface marker profile of hFCPCs, while showed some changes in the 3 lineages differentiation.
CONCLUSION
These results suggest that poly(I-C)-primed hFCPCs have an ability to modulate inflammatory response and OA phenotypes in vitro and encourage further studies to apply them in animal models of OA in the future.
Topics: Animals; Humans; Interleukin-1beta; Poly I-C; Osteoarthritis; Cartilage; Stem Cells; Phenotype
PubMed: 35932427
DOI: 10.1007/s13770-022-00478-w -
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 Jan 2021Several factors, including bacterial and viral infections, have been associated with rhinosinusitis and nasal tissue remodelling that may result in nasal polyp...
Several factors, including bacterial and viral infections, have been associated with rhinosinusitis and nasal tissue remodelling that may result in nasal polyp formation. However, the potential role of bacterial or viral stimuli triggering polyp development is unclear. Here, we used lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid [poly(I:C)] in a murine model of allergic rhinosinusitis to compare different effects of bacterial- and virus-derived stimuli in the pathogenesis of nasal polyp formation. Briefly, BALB/c mice were sensitised and challenged with ovalbumin and staphylococcal enterotoxin, with or without LPS or poly(I:C), and the consequent histopathological profiles, cytokines, and systemic humoral responses were studied. While no significant differences in polyp formations and epithelial disruptions were observed among the experimental groups, the local cell recruitment patterns slightly differed in animals that received either LPS or poly(I:C). Additionally, the local immune environments generated by LPS or poly(I:C) stimulation varied. LPS stimulation induced a marked Th1/Th17 response and predominantly neutrophilic nasal polyp formations, whereas poly(I:C) induced a Th2-skewed environment in neutrophilic nasal polyp development. Overall, our findings show that both cell recruitment patterns and local immune environments induced by these two stimuli differ, which may have implications in the physiopathology of rhinosinusitis with nasal polyp.
Topics: Animals; Cytokines; Disease Models, Animal; Enterotoxins; Humans; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Nasal Mucosa; Nasal Polyps; Neutrophils; Ovalbumin; Poly I-C; Rhinitis, Allergic; Sinusitis; T-Lymphocyte Subsets
PubMed: 33441902
DOI: 10.1038/s41598-020-80483-y -
Molecular Immunology Nov 2023Fish RTP3, belonging to the receptor-transporting protein family, display several functions, including a putative antiviral role as virus-responsive gene. In this work,...
Fish RTP3, belonging to the receptor-transporting protein family, display several functions, including a putative antiviral role as virus-responsive gene. In this work, we have identified and characterized two different European sea bass rtp3 genes. In addition, an in vivo transcription analysis in response to LPS, poly I:C and betanodavirus infection (RGNNV genotype) has been performed. The sequence analysis showed that European sea bass displays two rtp3 genes, X1 and X2, composed of two exons and a single intron (1007-bp and 888-bp long, respectively), located within the ORF sequence. The full-length cDNA is 1969 bp for rtp3 X1, and 1491 bp for rtp3 X2. Several ATTTA motifs have been found in the intron sequence of both genes, whereas rtp3 X1 also contains this motif in both untranslated regions. The transcription analyses revealed significant level of rtp3 X2 mRNA in brain and head kidney after LPS and poly I:C inoculation; however, the induction elicited by RGNNV infection was much higher, suggesting an essential role for this protein in controlling NNV infections.
Topics: Animals; Bass; Lipopolysaccharides; Genomics; Genotype; Poly I-C; Fish Diseases; Nodaviridae; RNA Virus Infections
PubMed: 37879238
DOI: 10.1016/j.molimm.2023.10.009 -
Journal of Immunology (Baltimore, Md. :... Oct 2022Type I conventional dendritic cells (cDC1s) are an essential Ag-presenting population required for generating adaptive immunity against intracellular pathogens and...
Type I conventional dendritic cells (cDC1s) are an essential Ag-presenting population required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli regulate cDC1 function remain unclear. We previously demonstrated that the cytokine-responsive transcriptional regulator STAT3 inhibits polyinosinic:polycytidylic acid [poly(I:C)]-induced cDC1 maturation and cDC1-mediated antitumor immunity in murine breast cancer, indicating an intrinsic, suppressive role for STAT3 in cDC1s. To probe transcriptional mechanisms regulating cDC1 function, we generated novel RNA sequencing datasets representing poly(I:C)-, IL-10-, and STAT3-mediated gene expression responses in murine cDC1s. Bioinformatics analyses indicated that poly(I:C) stimulates multiple inflammatory pathways independent of STAT3, while IL-10-activated STAT3 uniquely inhibits the poly(I:C)-induced type I IFN (IFN-I) transcriptional response. We validated this mechanism using purified cDC1s deficient for STAT3 or IFN signaling. Our data reveal IL-10-activated STAT3 suppresses production of IFN-β and IFN-γ, accrual of tyrosine phosphorylated STAT1, and IFN-stimulated gene expression in cDC1s after poly(I:C) exposure. Moreover, we found that maturation of cDC1s in response to poly(I:C) is dependent on the IFN-I receptor, but not the type II IFN receptor, or IFN-λ. Taken together, we elucidate an essential role for STAT3 in restraining autocrine IFN-I signaling in cDC1s elicited by poly(I:C) stimulation, and we provide novel RNA sequencing datasets that will aid in further delineating inflammatory and anti-inflammatory mechanisms in cDC1s.
Topics: Animals; Cytokines; Dendritic Cells; Interleukin-10; Mice; Poly I-C; STAT3 Transcription Factor; Tyrosine
PubMed: 36038291
DOI: 10.4049/jimmunol.2101104 -
EMBO Molecular Medicine May 2024Radiotherapy (RT) has been reported to induce abscopal effect in advanced hepatocellular carcinoma (HCC), but such phenomenon was only observed in sporadic cases. Here,...
Radiotherapy (RT) has been reported to induce abscopal effect in advanced hepatocellular carcinoma (HCC), but such phenomenon was only observed in sporadic cases. Here, we demonstrated that subcutaneous administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) could strengthen the abscopal effect during RT through activating tumor cell ferroptosis signals in bilateral HCC subcutaneous tumor mouse models, which could be significantly abolished by TLR3 knock-out or ferroptosis inhibitor ferrostatin-1. Moreover, poly(I:C) could promote the presentation of tumor neoantigens by dendritic cells to enhance the recruitment of activated CD8 T cells into distant tumor tissues for inducing tumor cell ferroptosis during RT treatment. Finally, the safety and feasibility of combining poly(I:C) with RT for treating advanced HCC patients were further verified in a prospective clinical trial. Thus, enhancing TLR3 signaling activation during RT could provide a novel strategy for strengthening abscopal effect to improve the clinical benefits of advanced HCC patients.
Topics: Toll-Like Receptor 3; Animals; Ferroptosis; Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Mice; Poly I-C; Male; Female; Cell Line, Tumor; Mice, Inbred C57BL; Disease Models, Animal; Mice, Knockout; Middle Aged
PubMed: 38671318
DOI: 10.1038/s44321-024-00068-4 -
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 -
Cytosolic dsRNA improves neonatal innate immune responses to adjuvants in use in pediatric vaccines.Journal of Leukocyte Biology Sep 2022Pattern recognition receptors (PRRs) of the innate immune system represent the critical front-line defense against pathogens, and new vaccine formulations target these...
Pattern recognition receptors (PRRs) of the innate immune system represent the critical front-line defense against pathogens, and new vaccine formulations target these PRR pathways to boost vaccine responses, through activation of cellular/Th1 immunity. The majority of pediatric vaccines contain aluminum (ALUM) or monophosphoryl lipid A (MPLA) as adjuvants to encourage immune activation. Evidence suggests that elements of the innate immune system, currently being targeted for vaccine adjuvanticity do not fully develop until puberty and it is likely that effective adjuvants for the neonatal and pediatric populations are being overlooked due to modeling of responses in adult systems. We recently reported that the activity of the cytosolic nucleic acid (CNA) sensing family of PRRs is strong in cord blood and peripheral blood of young children. This study investigates the function of CNA sensors in subsets of neonatal innate immune cells and shows that myeloid cells from cord blood can be activated to express T cell costimulatory markers, and also to produce Th1 promoting cytokines. CD80 and CD86 were consistently up-regulated in response to cytosolic Poly(I:C) stimulation in all cell types examined and CNA activation also induced robust Type I IFN and low levels of TNFα in monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells. We have compared CNA activation to adjuvants currently in use (MPLA or ALUM), either alone or in combination and found that cytosolic Poly(I:C) in combination with MPLA or ALUM can improve expression of activation marker levels above those observed with either adjuvant alone. This may prove particularly promising in the context of improving the efficacy of existing ALUM- or MPLA-containing vaccines, through activation of T cell-mediated immunity.
Topics: Adjuvants, Immunologic; Adult; Child; Child, Preschool; Cytokines; Humans; Immunity, Cellular; Immunity, Innate; Infant, Newborn; Poly I-C; Receptors, Pattern Recognition; Vaccines
PubMed: 35098572
DOI: 10.1002/JLB.5A0521-242R -
FEBS Letters Nov 2021Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (or the synthetic dsRNA analog poly I:C) and induces a signal transduction pathway that results in...
Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (or the synthetic dsRNA analog poly I:C) and induces a signal transduction pathway that results in activation of transcription factors that induce expression of antiviral genes including type I interferon (IFN-I). Secreted IFN-I positively feeds back to amplify antiviral gene expression. In this report, we study the role of MEK/ERK MAP kinase in modulating antiviral gene expression downstream of TLR3. We find MEK/ERK is a negative regulator of antiviral gene expression by limiting expression of IFN-β. However, MEK/ERK does not limit antiviral responses downstream of the type I interferon receptor. These findings provide insights into regulatory mechanisms of antiviral gene expression and reveal potential targets for modulating antiviral immunity.
Topics: Animals; Antiviral Agents; Extracellular Signal-Regulated MAP Kinases; Interferon-beta; Mice; Poly I-C; RAW 264.7 Cells
PubMed: 34591979
DOI: 10.1002/1873-3468.14200