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Biomaterials Feb 2021Immunotherapy is one of the most promising approaches to inhibit tumor growth and metastasis by activating host immune functions. However, the arising problems such as...
Immunotherapy is one of the most promising approaches to inhibit tumor growth and metastasis by activating host immune functions. However, the arising problems such as low immune response caused by complex tumor microenvironment and extremely systemic immune storm still limit the clinical applications of immunotherapy. Here, we construct Poly I: C-encapsulated poly (lactic-co-glycolic acid) nanoparticles (PLP NPs) with a slow release profile. A biomimetic system (MPLP), which loads PLP NPs on the surface of bone marrow-derived macrophage (BMDM) via the maleimide-thiol conjugation, is synthesized to effectively deliver PLP, control drug release and activate the tumor-specific immune response in situ. The results show that PLP NPs loading does not affect the activity and function of BMDM. Then, BMDM acts as a living cell drug vehicle and promotes the accumulation of PLP NPs in tumors, where Poly I: C is released from PLP NPs and reprograms BMDM into tumoricidal M1 macrophage. Furthermore, MPLP triggers potent antitumor immune responses in vivo and effectively inhibits local and metastatic tumors without causing adverse pathological immune reactions. This study offers an inspiration to facilitate clinical translation through the delivery of drugs by living immune cells for future anticancer therapy.
Topics: Cell Line, Tumor; Immunotherapy; Macrophages; Nanoparticles; Pharmaceutical Preparations; Poly I-C; Polylactic Acid-Polyglycolic Acid Copolymer
PubMed: 33485214
DOI: 10.1016/j.biomaterials.2021.120670 -
Frontiers in Immunology 2020Tumor-associated macrophages (TAMs), with M2-like immunosuppressive profiles, are key players in the development and dissemination of tumors. Hence, the induction of M1...
Tumor-associated macrophages (TAMs), with M2-like immunosuppressive profiles, are key players in the development and dissemination of tumors. Hence, the induction of M1 pro-inflammatory and anti-tumoral states is critical to fight against cancer cells. The activation of the endosomal toll-like receptor 3 by its agonist poly(I:C) has shown to efficiently drive this polarization process. Unfortunately, poly(I:C) presents significant systemic toxicity, and its clinical use is restricted to a local administration. Therefore, the objective of this work has been to facilitate the delivery of poly(I:C) to macrophages through the use of nanotechnology, that will ultimately drive their phenotype toward pro-inflammatory states. Poly(I:C) was complexed to arginine-rich polypeptides, and then further enveloped with an anionic polymeric layer either by film hydration or incubation. Physicochemical characterization of the nanocomplexes was conducted by dynamic light scattering and transmission electron microscopy, and poly(I:C) association efficiency by gel electrophoresis. Primary human-derived macrophages were used as relevant cell model. Alamar Blue assay, ELISA, PCR and flow cytometry were used to determine macrophage viability, polarization, chemokine secretion and uptake of nanocomplexes. The cytotoxic activity of pre-treated macrophages against PANC-1 cancer cells was assessed by flow cytometry. The final poly(I:C) nanocomplexes presented sizes lower than 200 nm, with surface charges ranging from +40 to -20 mV, depending on the envelopment. They all presented high poly(I:C) loading values, from 12 to 50%, and great stability in cell culture media. , poly(I:C) nanocomplexes were highly taken up by macrophages, in comparison to the free molecule. Macrophage treatment with these nanocomplexes did not reduce their viability and efficiently stimulated the secretion of the T-cell recruiter chemokines CXCL10 and CCL5, of great importance for an effective anti-tumor immune response. Finally, poly(I:C) nanocomplexes significantly increased the ability of treated macrophages to directly kill cancer cells. Overall, these enveloped poly(I:C) nanocomplexes might represent a therapeutic option to fight cancer through the induction of cytotoxic M1-polarized macrophages.
Topics: Arginine; Cell Differentiation; Humans; Macrophage Activation; Nanoparticles; Poly I-C; Tumor-Associated Macrophages
PubMed: 32733469
DOI: 10.3389/fimmu.2020.01412 -
Scientific Reports Nov 2023Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive IL-6 production by...
Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive IL-6 production by SARS-Cov-2 infection remains unclear. Respiratory viruses initially infect nasal or bronchial epithelial cells that produce various inflammatory mediators. Here, we show that pretreatment of human bronchial epithelial cells (NCl-H292) with interferon (IFN)-γ (10 ng/mL) markedly increased IL-6 production induced by the toll-like receptor (TLR) 3 agonist poly(I:C) (1 µg/mL) from 0.4 ± 0.1 to 4.1 ± 0.4 ng/mL (n = 3, P < 0.01). A similar effect was observed in human alveolar A549 and primary bronchial epithelial cells. TLR3 knockdown using siRNA in NCl-H292 cells diminished the priming effects of IFN-γ on poly(I:C)-induced IL-6 production. Furthermore, the Janus kinase (JAK) inhibitor tofacitinib (1 µM) inhibited IFN-γ-induced upregulation of TLR3, and suppressed poly(I:C)-induced IL-6 production. Quantitative chromatin immunoprecipitation revealed that IFN-γ stimulated histone modifications at the IL-6 gene locus. Finally, IFN-γ priming significantly increased lung IL-6 mRNA and protein levels in poly(I:C)-administrated mice. Thus, priming bronchial epithelial cells with IFN-γ increases poly(I:C)-induced IL-6 production via JAK-dependent TLR3 upregulation and chromatin remodeling at the IL-6 gene locus. These mechanisms may be involved in severe respiratory inflammation following infection with RNA viruses.
Topics: Animals; Humans; Mice; Epithelial Cells; Interferon-gamma; Interleukin-6; Interleukin-8; Poly I-C; Toll-Like Receptor 3
PubMed: 38030681
DOI: 10.1038/s41598-023-48422-9 -
Fish & Shellfish Immunology Apr 2023Groupers are important mariculture fish in South China and Southeast Asian countries. However, the increasing frequency of infectious disease outbreaks has caused great...
Groupers are important mariculture fish in South China and Southeast Asian countries. However, the increasing frequency of infectious disease outbreaks has caused great economic losses in the grouper industry. Among these pathogens, Singapore grouper iridovirus (SGIV) infection causes high mortality in larval and juvenile stages of grouper. However, the mechanism underlying the action of viral manipulation on cellular immune response still remained largely uncertain. Here, using RNA-seq technology, we investigated the regulatory roles of SGIV infection on synthetic RNA duplex poly I:C induced immune response in vitro. Using reporter gene assays, we found that SGIV infection decreased poly I:C induced interferon promoter activation. Transcriptomic analysis showed that the mRNA expression levels of 2238 genes were up-regulated, while 1247 genes were down-regulated in poly I:C transfected grouper spleen (GS) cells. Interestingly, SGIV infection decreased the expression of 1479 up-regulated genes and increased the expression of 297 down-regulated genes in poly I:C transfected cells. The differentially expressed genes (DEGs) down-regulated by SGIV were directly related to immune, inflammation and viral infection, and JUN, STAT1, NFKB1, MAPK14A, TGFB1 and MX were the 6 top hub genes in the down-regulated DEGs' protein-protein interaction (PPI) network. Furthermore, quantitative real-time PCR (qPCR) analysis confirmed that the interferon signaling and inflammatory-related genes, including cGAS, STING, TBK1, MAVS, TNF, IRAK4 and NOD2 were up-regulated by poly I:C stimulation, but all significantly down-regulated after SGIV infection. Thus, we speculated that SGIV infection counteracted poly I:C induced antiviral immune response and this ability helped itself to escape host immune surveillance. Together, our data will contribute greatly to understanding the potential immune evasion mechanism of iridovirus infection in vitro.
Topics: Animals; Iridovirus; Bass; Antiviral Agents; Cloning, Molecular; Singapore; Ranavirus; Poly I-C; Immunity, Innate; Interferons; Fish Diseases; DNA Virus Infections; Fish Proteins
PubMed: 36921879
DOI: 10.1016/j.fsi.2023.108685 -
Physiology & Behavior Apr 2021Central fatigue is a condition associated with impairment of the central nervous system often leading to the manifestation of a range of debilitating symptoms. Fatigue...
Central fatigue is a condition associated with impairment of the central nervous system often leading to the manifestation of a range of debilitating symptoms. Fatigue can be a consequence of systemic inflammation following an infection. Administration of lipopolysaccharide (LPS) and polyriboinosinic:polyribocytidlic (poly I:C) to animals can induce systemic inflammation by mimicking a bacterial or viral infection respectively and therefore have been used as models of fatigue. We evaluated a range of phenotypic behaviors exhibited in the LPS and poly I:C animal models to assess whether they adequately replicate fatigue symptomology in humans. In addition to standard observation- and intervention-based behavioral assessments, we used powerful in-cage monitoring technology to quantify rodent behavior without external interference. LPS and poly I:C treated Sprague Dawley rats displayed 'sickness behaviors' of elevated temperature, weight loss and reduced activity in the open field test and with in-cage monitoring within 24 h post-treatment, but only LPS-treated rats displayed these behaviors beyond these acute timepoints. Once sickness behavior diminished, LPS-treated rats exhibited an increase in reward-seeking and motivation behaviors. Overall, these results suggest that the LPS animal model produces an extensive and sustained fatigue-like phenotype, whereas the poly I:C model only produced acute effects. Our results suggest that the LPS animal model is a more suitable candidate for further studies on central fatigue-like behavior.
Topics: Animals; Behavior, Animal; Disease Models, Animal; Fatigue; Illness Behavior; Lipopolysaccharides; Poly I-C; Rats; Rats, Sprague-Dawley
PubMed: 33529685
DOI: 10.1016/j.physbeh.2021.113347 -
Scientific Reports May 2023Most individuals with neurodevelopmental disorders (NDDs), including schizophrenia and autism spectrum disorders, experience disruptions in sleep and circadian rhythms....
Most individuals with neurodevelopmental disorders (NDDs), including schizophrenia and autism spectrum disorders, experience disruptions in sleep and circadian rhythms. Epidemiological studies indicate that exposure to prenatal infection increases the risk of developing NDDs. We studied how environmental circadian disruption contributes to NDDs using maternal immune activation (MIA) in mice, which models prenatal infection. Pregnant dams were injected with viral mimetic poly IC (or saline) at E9.5. Adult poly IC- and saline-exposed offspring were subjected to 4 weeks of each of the following: standard lighting (LD1), constant light (LL) and standard lighting again (LD2). Behavioral tests were conducted in the last 12 days of each condition. Poly IC exposure led to significant behavioral differences, including reduced sociability (males only) and deficits in prepulse inhibition. Interestingly, poly IC exposure led to reduced sociability specifically when males were tested after LL exposure. Mice were exposed again to either LD or LL for 4 weeks and microglia were characterized. Notably, poly IC exposure led to increased microglial morphology index and density in dentate gyrus, an effect attenuated by LL exposure. Our findings highlight interactions between circadian disruption and prenatal infection, which has implications in informing the development of circadian-based therapies for individuals with NDDs.
Topics: Pregnancy; Female; Male; Humans; Mice; Animals; Prenatal Exposure Delayed Effects; Poly I-C; Prepulse Inhibition; Schizophrenia; Behavior, Animal; Disease Models, Animal
PubMed: 37179433
DOI: 10.1038/s41598-023-34363-w -
Advanced Science (Weinheim,... Nov 2023The efficient activation of professional antigen-presenting cells-such as dendritic cells (DC)-in tumors and lymph nodes is critical for the design of next-generation...
The efficient activation of professional antigen-presenting cells-such as dendritic cells (DC)-in tumors and lymph nodes is critical for the design of next-generation cancer vaccines and may be able to provide anti-tumor effects by itself through immune stimulation. The challenge is to stimulate these cells without causing excessive toxicity. It is hypothesized that a multi-pronged combinatorial approach to DC stimulation would allow dose reductions of innate immune receptor-stimulating TLR3 agonists while enhancing drug efficacy. Here, a hybrid lipid nanoparticle (LNP) platform is developed and tested for double-stranded RNA (polyinosinic:polycytidylic acid for TLR3 agonism) and immune modulator (L-CANDI) delivery. This study shows that the ≈120 nm hybrid nanoparticles-in-nanoparticles effectively eradicate tumors by themselves and generate long-lasting, durable anti-tumor immunity in mouse models.
Topics: Animals; Mice; Toll-Like Receptor 3; Poly I-C; Cancer Vaccines; Neoplasms; Dendritic Cells
PubMed: 37814359
DOI: 10.1002/advs.202303576 -
Journal of Controlled Release :... Mar 2022Adjuvant loaded nanoparticles are a potent strategy for developing effective combined cancer immunotherapies. A polyinosinic-polycytidylic acid (poly I:C) is a ligand...
Adjuvant loaded nanoparticles are a potent strategy for developing effective combined cancer immunotherapies. A polyinosinic-polycytidylic acid (poly I:C) is a ligand for toll-like receptor 3 and a promising cancer adjuvant. However, regarding intravenous administration, the potential for and the mechanism of poly I:C loaded nanoparticles as a cancer vaccine are largely unknown. We investigated the effects of using a combination of poly I:C and an antigen loaded liposome for cancer immunotherapy and a key process for achieving effective antitumor immunity of the liposome system under conditions of intravenous vaccination. A poly I:C and ovalbumin (OVA) loaded octaarginine (R8) modified liposome (PoIC/OVA-R8L) drastically inhibited the systemic cytokine production derived from the poly I:C intravenous injection. Treatment with PoIC/OVA-R8L improved the immune status in B16-OVA tumors to an inflamed immune status and induced a significant combined antitumor effect with the anti-programmed cell death 1 ligand (PD-L1). In a mechanistic analysis compared with a high dose of the free form of poly I:C, interestingly, local cytokine production, maturation of antigen presenting cells and antigen presentation were comparable. Conversely, significant differences were identified in the processes after OVA-specific CTL generation. Collectively, our findings have implications for the development of intravenous liposomal vaccines.
Topics: Adjuvants, Immunologic; Administration, Intravenous; Animals; Antigen Presentation; Cancer Vaccines; Cytokines; Dendritic Cells; Ligands; Liposomes; Mice; Mice, Inbred C57BL; Neoplasms; Ovalbumin; Poly I-C
PubMed: 35065157
DOI: 10.1016/j.jconrel.2022.01.020 -
Brain, Behavior, and Immunity Jan 2022Viral infections during pregnancy are associated with increased incidence of psychiatric disorders in offspring. The pathological outcomes of viral infection appear to...
Viral infections during pregnancy are associated with increased incidence of psychiatric disorders in offspring. The pathological outcomes of viral infection appear to be caused by the deleterious effects of innate immune response-associated factors on development of the fetus, which predispose the offspring to pathological conditions in adulthood. The negative impact of viral infections varies substantially between pregnancies. Here, we explored whether differential stress sensitivity underlies the high heterogeneity of immune reactivity and whether this may influence the pathological consequences of maternal immune activation. Using mouse models of social dominance (Dom) and submissiveness (Sub), which possess innate features of stress resilience and vulnerability, respectively, we identified differential immune reactivity to the synthetic analogue of viral double-stranded RNA, Poly(I:C), in Sub and Dom nulliparous and pregnant females. More specifically, we found that Sub females showed an exacerbated pro- and anti-inflammatory cytokine response to Poly(I:C) as compared with Dom females. Sub offspring born to Sub mothers (stress sensitive offspring) showed enhanced locomotory response to the non-competitive NMDA antagonist, MK-801, which was potentiated by prenatal Poly(I:C) exposure. Our findings suggest that inherited stress sensitivity may lead to functional changes in glutamatergic signaling, which in turn is further exacerbated by prenatal exposure to viral-like infection. The maternal immunome seems to play a crucial role in these observed phenomena.
Topics: Animals; Behavior, Animal; Cytokines; Disease Models, Animal; Female; Mice; Poly I-C; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 34547401
DOI: 10.1016/j.bbi.2021.09.004 -
Frontiers in Immunology 2023Viral pneumonia is a global health burden with a high mortality rate, especially in the elderly and in patients with underlying diseases. Recent studies have found that...
Viral pneumonia is a global health burden with a high mortality rate, especially in the elderly and in patients with underlying diseases. Recent studies have found that myeloid-derived suppressor cells (MDSCs) are abundant in these patient groups; however, their roles in the progression of viral pneumonia remain unclear. In this study, we observed a substantial increase in MDSCs in a mouse model of renal ischemia/reperfusion (I/R) injury and in older mice. When intranasal polyinosinic-polycytidylic acid (poly(I:C)) administration was used to mimic viral pneumonia, mice with renal I/R injury exhibited more severe lung inflammation than sham mice challenged with poly(I:C). In addition, MDSC depletion attenuated lung inflammation in mice with I/R injury. Similar results were obtained in older mice compared with those in young mice. Furthermore, adoptive transfer of in -differentiated MDSCs exacerbated poly(I:C)-induced lung inflammation. Taken together, these experimental results suggest that the increased proportion of MDSCs in mice with renal I/R injury and in older mice exacerbates poly(I:C)-induced lung inflammation. These findings have important implications for the treatment and prevention of severe lung inflammation caused by viral pneumonia.
Topics: Humans; Mice; Animals; Aged; Myeloid-Derived Suppressor Cells; Poly I-C; Kidney; Disease Models, Animal; Pneumonia, Viral
PubMed: 37818369
DOI: 10.3389/fimmu.2023.1243851