International Journal of Molecular Sciences

Research

18 pages, 5185 KiB

Open AccessArticle

Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19

by Gábor Kökény, Tamás Bakos, Bálint András Barta, Georgina Viktória Nagy, Tamás Mészáros, Gergely T. Kozma, András Szabó, János Szebeni, Béla Merkely and Tamás Radovits

Int. J. Mol. Sci. 2023, 24(2), 1138; https://doi.org/10.3390/ijms24021138 - 6 Jan 2023

Cited by 2 | Viewed by 2399

Abstract

Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known [...] Read more.

Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known stimulator of the innate immune system, could reproduce these changes in pigs. Pigs were instrumented for hemodynamic analysis and, after i.v. administration of zymosan, serial blood samples were taken to measure blood cell changes, cytokine gene transcription in PBMC and blood levels of inflammatory cytokines, using qPCR and ELISA. Zymosan bolus (0.1 mg/kg) elicited transient hemodynamic disturbance within minutes without detectable cytokine or blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This was followed by a transient granulopenia and then, up to 6 h, major granulocytosis, resulting in a 3–4-fold increase in NLR. These changes were paralleled by massive transcription and/or rise in IL-6, TNF-alpha, CCL-2, CXCL-10, and IL-1RA in blood. There was significant correlation between lymphopenia and IL-6 gene expression. We conclude that the presented model may enable mechanistic studies on late-stage COVID-19 and CSS, as well as streamlined drug testing against these conditions. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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18 pages, 2650 KiB

Open AccessArticle

Macrophages Release Extracellular Vesicles of Different Properties and Composition Following Exposure to Nanoparticles

by Sarah Deville, Hector Garcia Romeu, Eline Oeyen, Inge Mertens, Inge Nelissen and Anna Salvati

Int. J. Mol. Sci. 2023, 24(1), 260; https://doi.org/10.3390/ijms24010260 - 23 Dec 2022

Cited by 1 | Viewed by 2065

Abstract

Extracellular vesicles are membrane-bound carriers with complex cargoes, which play a major role in intercellular communication, for instance, in the context of the immune response. Macrophages are known to release extracellular vesicles in response to different stimuli, and changes in their size, number, [...] Read more.

Extracellular vesicles are membrane-bound carriers with complex cargoes, which play a major role in intercellular communication, for instance, in the context of the immune response. Macrophages are known to release extracellular vesicles in response to different stimuli, and changes in their size, number, and composition may provide important insights into the responses induced. Macrophages are also known to be highly efficient in clearing nanoparticles, when in contact with them, and in triggering the immune system. However, little is known about how the nature and composition of the vesicles released by these cells may vary upon nanoparticle exposure. In order to study this, in this work, alveolar-like macrophages were exposed to a panel of nanoparticles with varying surface and composition, including amino-modified and carboxylated polystyrene and plain silica. We previously showed that these nanoparticles induced very different responses in these cells. Here, experimental conditions were carefully tuned in order to separate the extracellular vesicles released by the macrophages several hours after exposure to sub-toxic concentrations of the same nanoparticles. After separation, different methods, including high-sensitivity flow cytometry, TEM imaging, Western blotting, and nanoparticle tracking analysis, were combined in order to characterize the extracellular vesicles. Finally, proteomics was used to determine their composition and how it varied upon exposure to the different nanoparticles. Our results show that depending on the nanoparticles’ properties. The macrophages produced extracellular vesicles of varying number, size, and protein composition. This indicates that macrophages release specific signals in response to nanoparticles and overall suggests that extracellular vesicles can reflect subtle responses to nanoparticles and nanoparticle impact on intercellular communication. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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15 pages, 2305 KiB

Open AccessArticle

Induction of Innate Memory in Human Monocytes Exposed to Mixtures of Bacterial Agents and Nanoparticles

by Giacomo Della Camera, Tinghao Liu, Wenjie Yang, Yang Li, Victor F. Puntes, Sabrina Gioria, Paola Italiani and Diana Boraschi

Int. J. Mol. Sci. 2022, 23(23), 14655; https://doi.org/10.3390/ijms232314655 - 24 Nov 2022

Viewed by 1433

Abstract

We assessed whether concomitant exposure of human monocytes to bacterial agents and different engineered nanoparticles can affect the induction of protective innate memory, an immune mechanism that affords better resistance to diverse threatening challenges. Monocytes were exposed in vitro to nanoparticles of different [...] Read more.

We assessed whether concomitant exposure of human monocytes to bacterial agents and different engineered nanoparticles can affect the induction of protective innate memory, an immune mechanism that affords better resistance to diverse threatening challenges. Monocytes were exposed in vitro to nanoparticles of different chemical nature, shape and size either alone or admixed with LPS, and cell activation was assessed in terms of production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). After return to baseline conditions, cells were re-challenged with LPS and their secondary “memory” response measured. Results show that nanoparticles alone are essentially unable to generate memory, while LPS induced a tolerance memory response (less inflammatory cytokines, equal or increased anti-inflammatory cytokines). LPS-induced tolerance was not significantly affected by the presence of nanoparticles during the memory generation phase, although with substantial donor-to-donor variability. This suggests that, despite the overall lack of significant effects on LPS-induced innate memory, nanoparticles may have donor-specific effects. Thus, future nanosafety assessment and nanotherapeutic strategies will need a personalized approach in order to ensure both the safety and efficacy of nano medical compounds for individual patients. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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29 pages, 4124 KiB

Open AccessArticle

Modulation of the Functional State of Mouse Neutrophils by Selenium Nanoparticles In Vivo

by Valentina N. Mal’tseva, Sergey V. Gudkov and Egor A. Turovsky

Int. J. Mol. Sci. 2022, 23(21), 13651; https://doi.org/10.3390/ijms232113651 - 7 Nov 2022

Cited by 7 | Viewed by 2029

Abstract

This study aimed to discover the immunomodulatory effect of selenium nanoparticles (SeNPs) on the functional state of neutrophils in vivo. Intraperitoneal injections of SeNPs (size 100 nm) 2.5 mg/kg/daily to BALB/c mice for a duration of 7–28 days led to the development of [...] Read more.

This study aimed to discover the immunomodulatory effect of selenium nanoparticles (SeNPs) on the functional state of neutrophils in vivo. Intraperitoneal injections of SeNPs (size 100 nm) 2.5 mg/kg/daily to BALB/c mice for a duration of 7–28 days led to the development of an inflammatory reaction, which was registered by a significant increase in the number of neutrophils released from the peritoneal cavity, as well as their activated state, without additional effects. At the same time, subcutaneous injections of the same SeNPs preparations at concentrations of 0.1, 0.5, and 2.5 mg/kg, on the contrary, modulated the functional state of neutrophils depending on the concentration and duration of SeNPs administration. With the use of fluorescence spectroscopy, chemiluminescence, biochemical methods, and PCR analysis, it was found that subcutaneous administration of SeNPs (0.1, 0.5, and 2.5 mg/kg) to mice for a short period of time (7–14 days) leads to modification of important neutrophil functions (adhesion, the number of migrating cells into the peritoneal cell cavity, ROS production, and NET formation). The obtained results indicated the immunostimulatory and antioxidant effects of SeNPs in vivo during short-term administration, while the most pronounced immunomodulatory effects of SeNPs were observed with the introduction of a low concentration of SeNPs (0.1 mg/kg). Increase in the administration time of SeNPs (0.1 mg/kg or 2.5 mg/kg) up to 28 days led to a decrease in the adhesive abilities of neutrophils and suppression of the expression of mRNA of adhesive molecules, as well as proteins involved in the generation of ROS, with the exception of NOX2; there was a tendency to suppress gene expression pro-inflammatory factors, which indicates the possible manifestation of immunosuppressive and anti-inflammatory effects of SeNPs during their long-term administration. Changes in the expression of selenoproteins also had features depending on the concentration and duration of the administered SeNPs. Selenoprotein P, selenoprotein M, selenoprotein S, selenoprotein K, and selenoprotein T were the most sensitive to the introduction of SeNPs into the mouse organism, which indicates their participation in maintaining the functional status of neutrophils, and possibly mediated the immunomodulatory effect of SeNPs. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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10 pages, 1330 KiB

Open AccessArticle

Monitoring Anti-PEG Antibodies Level upon Repeated Lipid Nanoparticle-Based COVID-19 Vaccine Administration

by Giuditta Guerrini, Sabrina Gioria, Aisha V. Sauer, Simone Lucchesi, Francesca Montagnani, Gabiria Pastore, Annalisa Ciabattini, Donata Medaglini and Luigi Calzolai

Int. J. Mol. Sci. 2022, 23(16), 8838; https://doi.org/10.3390/ijms23168838 - 9 Aug 2022

Cited by 32 | Viewed by 3557

Abstract

PEGylated lipids are one of the four constituents of lipid nanoparticle mRNA COVID-19 vaccines. Therefore, various concerns have been raised on the generation of anti-PEG antibodies and their potential role in inducing hypersensitivity reactions following vaccination or in reducing vaccine efficacy due to [...] Read more.

PEGylated lipids are one of the four constituents of lipid nanoparticle mRNA COVID-19 vaccines. Therefore, various concerns have been raised on the generation of anti-PEG antibodies and their potential role in inducing hypersensitivity reactions following vaccination or in reducing vaccine efficacy due to anti-carrier immunity. Here, we assess the prevalence of anti-PEG antibodies, in a cohort of vaccinated individuals, and give an overview of their time evolution after repeated vaccine administrations. Results indicate that, in our cohort, the presence of PEG in the formulation did not influence the level of anti-Spike antibodies generated upon vaccination and was not related to any reported, serious adverse effects. The time-course analysis of anti-PEG IgG showed no significant booster effect after each dose, whereas for IgM a significant increase in antibody levels was detected after the first and third dose. Data suggest that the presence of PEG in the formulation does not affect safety or efficacy of lipid-nanoparticle-based COVID-19 vaccines. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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22 pages, 7756 KiB

Open AccessArticle

Pathways Related to NLRP3 Inflammasome Activation Induced by Gold Nanorods

by Rob J. Vandebriel, Sylvie Remy, Jolanda P. Vermeulen, Evelien G. E. Hurkmans, Kirsten Kevenaar, Neus G. Bastús, Beatriz Pelaz, Mahmoud G. Soliman, Victor F. Puntes, Wolfgang J. Parak, Jeroen L. A. Pennings and Inge Nelissen

Int. J. Mol. Sci. 2022, 23(10), 5763; https://doi.org/10.3390/ijms23105763 - 20 May 2022

Cited by 2 | Viewed by 2035

Abstract

The widespread and increasing use of engineered nanomaterials (ENM) increases the risk of human exposure, generating concern that ENM may provoke adverse health effects. In this respect, their physicochemical characteristics are critical. The immune system may respond to ENM through inflammatory reactions. The [...] Read more.

The widespread and increasing use of engineered nanomaterials (ENM) increases the risk of human exposure, generating concern that ENM may provoke adverse health effects. In this respect, their physicochemical characteristics are critical. The immune system may respond to ENM through inflammatory reactions. The NLRP3 inflammasome responds to a wide range of ENM, and its activation is associated with various inflammatory diseases. Recently, anisotropic ENM have become of increasing interest, but knowledge of their effects on the immune system is still limited. The objective of the study was to compare the effects of gold ENM of different shapes on NLRP3 inflammasome activation and related signalling pathways. Differentiated THP-1 cells (wildtype, ASC- or NLRP3-deficient), were exposed to PEGylated gold nanorods, nanostars, and nanospheres, and, thus, also different surface chemistries, to assess NLRP3 inflammasome activation. Next, the exposed cells were subjected to gene expression analysis. Nanorods, but not nanostars or nanospheres, showed NLRP3 inflammasome activation. ASC- or NLRP3-deficient cells did not show this effect. Gene Set Enrichment Analysis revealed that gold nanorod-induced NLRP3 inflammasome activation was accompanied by downregulated sterol/cholesterol biosynthesis, oxidative phosphorylation, and purinergic receptor signalling. At the level of individual genes, downregulation of Paraoxonase-2, a protein that controls oxidative stress, was most notable. In conclusion, the shape and surface chemistry of gold nanoparticles determine NLRP3 inflammasome activation. Future studies should include particle uptake and intracellular localization. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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15 pages, 2766 KiB

Open AccessArticle

Ex Vivo Human Colon Tissue Exposure to Pristine Graphene Activates Genes Involved in the Binding, Adhesion and Proliferation of Epithelial Cells

by Mohamed H. Lahiani, Kuppan Gokulan, Katherine Williams and Sangeeta Khare

Int. J. Mol. Sci. 2021, 22(21), 11443; https://doi.org/10.3390/ijms222111443 - 23 Oct 2021

Cited by 4 | Viewed by 2039

Abstract

Toxicology studies on pristine graphene are limited and lack significant correlations with actual human response. The goal of the current study was to determine the response of total colonic human tissue to pristine graphene exposure. Biopsy punches of colon tissues from healthy human [...] Read more.

Toxicology studies on pristine graphene are limited and lack significant correlations with actual human response. The goal of the current study was to determine the response of total colonic human tissue to pristine graphene exposure. Biopsy punches of colon tissues from healthy human were used to assess the biological response after ex vivo exposure to graphene at three different concentrations (1, 10, and 100 µg/mL). mRNA expression of specific genes or intestinal cytokine abundance was assessed using real-time PCR or multiplex immunoassays, respectively. Pristine graphene-activated genes that are related to binding and adhesion (GTPase and KRAS) within 2 h of exposure. Furthermore, the PCNA (proliferating cell nuclear antigen) gene was upregulated after exposure to graphene at all concentrations. Ingenuity pathway analysis revealed that STAT3 and VEGF signaling pathways (known to be involved in cell proliferation and growth) were upregulated. Graphene exposure (10 µg/mL) for 24 h significantly increased levels of pro-inflammatory cytokines IFNγ, IL-8, IL-17, IL-6, IL-9, MIP-1α, and Eotaxin. Collectively, these results indicated that graphene may activate the STAT3–IL23–IL17 response axis. The findings in this study provide information on toxicity evaluation using a human-relevant ex vivo colon model and serve as a basis for further exploration of its bio-applications. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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18 pages, 3287 KiB

Open AccessArticle

Impact of Differentiated Macrophage-Like Cells on the Transcriptional Toxicity Profile of CuO Nanoparticles in Co-Cultured Lung Epithelial Cells

by Matthias Hufnagel, Ronja Neuberger, Johanna Wall, Martin Link, Alexandra Friesen and Andrea Hartwig

Int. J. Mol. Sci. 2021, 22(9), 5044; https://doi.org/10.3390/ijms22095044 - 10 May 2021

Cited by 14 | Viewed by 3328

Abstract

To mimic more realistic lung tissue conditions, co-cultures of epithelial and immune cells are one comparatively easy-to-use option. To reveal the impact of immune cells on the mode of action (MoA) of CuO nanoparticles (NP) on epithelial cells, A549 cells as a model [...] Read more.

To mimic more realistic lung tissue conditions, co-cultures of epithelial and immune cells are one comparatively easy-to-use option. To reveal the impact of immune cells on the mode of action (MoA) of CuO nanoparticles (NP) on epithelial cells, A549 cells as a model for epithelial cells have been cultured with or without differentiated THP-1 cells, as a model for macrophages. After 24 h of submerged incubation, cytotoxicity and transcriptional toxicity profiles were obtained and compared between the cell culture systems. Dose-dependent cytotoxicity was apparent starting from 8.0 µg/cm² CuO NP. With regard to gene expression profiles, no differences between the cell models were observed concerning metal homeostasis, oxidative stress, and DNA damage, confirming the known MoA of CuO NP, i.e., endocytotic particle uptake, intracellular particle dissolution within lysosomes with subsequent metal ion deliberation, increased oxidative stress, and genotoxicity. However, applying a co-culture of epithelial and macrophage-like cells, CuO NP additionally provoked a pro-inflammatory response involving NLRP3 inflammasome and pro-inflammatory transcription factor activation. This study demonstrates that the application of this easy-to-use advanced in vitro model is able to extend the detection of cellular effects provoked by nanomaterials by an immunological response and emphasizes the use of such models to address a more comprehensive MoA. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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20 pages, 3741 KiB

Open AccessArticle

Complement-Opsonized Nano-Carriers Are Bound by Dendritic Cells (DC) via Complement Receptor (CR)3, and by B Cell Subpopulations via CR-1/2, and Affect the Activation of DC and B-1 Cells

by Monika Bednarczyk, Carolina Medina-Montano, Frederic Julien Fittler, Henner Stege, Meike Roskamp, Michael Kuske, Christian Langer, Marco Vahldieck, Evelyn Montermann, Ingrid Tubbe, Nadine Röhrig, Andrzej Dzionek, Stephan Grabbe and Matthias Bros

Int. J. Mol. Sci. 2021, 22(6), 2869; https://doi.org/10.3390/ijms22062869 - 11 Mar 2021

Cited by 13 | Viewed by 3010

Abstract

The development of nanocarriers (NC) for biomedical applications has gained large interest due to their potential to co-deliver drugs in a cell-type-targeting manner. However, depending on their surface characteristics, NC accumulate serum factors, termed protein corona, which may affect their cellular binding. We [...] Read more.

The development of nanocarriers (NC) for biomedical applications has gained large interest due to their potential to co-deliver drugs in a cell-type-targeting manner. However, depending on their surface characteristics, NC accumulate serum factors, termed protein corona, which may affect their cellular binding. We have previously shown that NC coated with carbohydrates to enable biocompatibility triggered the lectin-dependent complement pathway, resulting in enhanced binding to B cells via complement receptor (CR)1/2. Here we show that such NC also engaged all types of splenic leukocytes known to express CR3 at a high rate when NC were pre-incubated with native mouse serum resulting in complement opsonization. By focusing on dendritic cells (DC) as an important antigen-presenting cell type, we show that CR3 was essential for binding/uptake of complement-opsonized NC, whereas CR4, which in mouse is specifically expressed by DC, played no role. Further, a minor B cell subpopulation (B-1), which is important for first-line pathogen responses, and co-expressed CR1/2 and CR3, in general, engaged NC to a much higher extent than normal B cells. Here, we identified CR-1/2 as necessary for binding of complement-opsonized NC, whereas CR3 was dispensable. Interestingly, the binding of complement-opsonized NC to both DC and B-1 cells affected the expression of activation markers. Our findings may have important implications for the design of nano-vaccines against infectious diseases, which codeliver pathogen-specific protein antigen and adjuvant, aimed to induce a broad adaptive cellular and humoral immune response by inducing cytotoxic T lymphocytes that kill infected cells and pathogen-neutralizing antibodies, respectively. Decoration of nano-vaccines either with carbohydrates to trigger complement activation in vivo or with active complement may result in concomitant targeting of DC and B cells and thereby may strongly enhance the extent of dual cellular/humoral immune responses. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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23 pages, 2532 KiB

Open AccessArticle

A Step-by-Step Approach to Improve Clinical Translation of Liposome-Based Nanomaterials, a Focus on Innate Immune and Inflammatory Responses

by Giacomo Della Camera, Dorelia Lipsa, Dora Mehn, Paola Italiani, Diana Boraschi and Sabrina Gioria

Int. J. Mol. Sci. 2021, 22(2), 820; https://doi.org/10.3390/ijms22020820 - 15 Jan 2021

Cited by 11 | Viewed by 2604

Abstract

This study aims to provide guidelines to design and perform a robust and reliable physical-chemical characterization of liposome-based nanomaterials, and to support method development with a specific focus on their inflammation-inducing potential. Out of eight differently functionalized liposomes selected as “case-studies”, three passed [...] Read more.

This study aims to provide guidelines to design and perform a robust and reliable physical-chemical characterization of liposome-based nanomaterials, and to support method development with a specific focus on their inflammation-inducing potential. Out of eight differently functionalized liposomes selected as “case-studies”, three passed the physical-chemical characterization (in terms of size-distribution, homogeneity and stability) and the screening for bacterial contamination (sterility and apyrogenicity). Although all three were non-cytotoxic when tested in vitro, they showed a different capacity to activate human blood cells. HSPC/CHOL-coated liposomes elicited the production of several inflammation-related cytokines, while DPPC/CHOL- or DSPC/CHOL-functionalized liposomes did not. This work underlines the need for accurate characterization at multiple levels and the use of reliable in vitro methods, in order to obtain a realistic assessment of liposome-induced human inflammatory response, as a fundamental requirement of nanosafety regulations. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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21 pages, 3704 KiB

Open AccessArticle

Characterization of Urine Stem Cell-Derived Extracellular Vesicles Reveals B Cell Stimulating Cargo

by Asmaa A. Zidan, Mohammed Al-Hawwas, Griffith B. Perkins, Ghada M. Mourad, Catherine J. M. Stapledon, Larisa Bobrovskaya, Xin-Fu Zhou and Plinio R. Hurtado

Int. J. Mol. Sci. 2021, 22(1), 459; https://doi.org/10.3390/ijms22010459 - 5 Jan 2021

Cited by 17 | Viewed by 4556

Abstract

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. [...] Read more.

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC–derived EVs are a heterogeneous population, ranging in size from that of micro–vesicles (150 nm–1 μm) down to that of exosomes (60–150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60–150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL–6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)–derived EVs previously described, suppressing T cell response to activation. The finding that USC–derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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15 pages, 3064 KiB

Open AccessArticle

Human Intestinal Tissue Explant Exposure to Silver Nanoparticles Reveals Sex Dependent Alterations in Inflammatory Responses and Epithelial Cell Permeability

by Kuppan Gokulan, Katherine Williams, Sarah Orr and Sangeeta Khare

Int. J. Mol. Sci. 2021, 22(1), 9; https://doi.org/10.3390/ijms22010009 - 22 Dec 2020

Cited by 14 | Viewed by 2526

Abstract

Consumer products manufactured with antimicrobial silver nanoparticles (AgNPs) may affect the gastrointestinal (GI) system. The human GI-tract is complex and there are physiological and anatomical differences between human and animal models that limit comparisons between species. Thus, assessment of AgNP toxicity on the [...] Read more.

Consumer products manufactured with antimicrobial silver nanoparticles (AgNPs) may affect the gastrointestinal (GI) system. The human GI-tract is complex and there are physiological and anatomical differences between human and animal models that limit comparisons between species. Thus, assessment of AgNP toxicity on the human GI-tract may require tools that allow for the examination of subtle changes in inflammatory markers and indicators of epithelial perturbation. Fresh tissues were excised from the GI-tract of human male and female subjects to evaluate the effects of AgNPs on the GI-system. The purpose of this study was to perform an assessment on the ability of the ex vivo model to evaluate changes in levels of pro-/anti-inflammatory cytokines/chemokines and mRNA expression of intestinal permeability related genes induced by AgNPs in ileal tissues. The ex vivo model preserved the structural and biological functions of the in-situ organ. Analysis of cytokine expression data indicated that intestinal tissue of male and female subjects responded differently to AgNP treatment, with male samples showing significantly elevated Granulocyte-macrophage colony-stimulating factor (GM-CSF) after treatment with 10 nm and 20 nm AgNPs for 2 h and significantly elevated RANTES after treatment with 20 nm AgNPs for 24 h. In contrast, tissues of female showed no significant effects of AgNP treatment at 2 h and significantly decreased RANTES (20 nm), TNF-α (10 nm), and IFN-γ (10 nm) at 24 h. Smaller size AgNPs (10 nm) perturbed more permeability-related genes in samples of male subjects, than in samples from female subjects. In contrast, exposure to 20 nm AgNPs resulted in upregulation of a greater number of genes in female-derived samples (36 genes) than in male-derived samples (8 genes). The ex vivo tissue model can distinguish sex dependent effects of AgNP and could serve as a translational non-animal model to assess the impacts of xenobiotics on human intestinal mucosa. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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16 pages, 5046 KiB

Open AccessArticle

Gingival Response to Dental Implant: Comparison Study on the Effects of New Nanopored Laser-Treated vs. Traditional Healing Abutments

by Barbara Ghinassi, Angela Di Baldassarre, Gianmaria D’Addazio, Tonino Traini, Mauro Andrisani, Giorgio Di Vincenzo, Giulia Gaggi, Maurizio Piattelli, Sergio Caputi and Bruna Sinjari

Int. J. Mol. Sci. 2020, 21(17), 6056; https://doi.org/10.3390/ijms21176056 - 22 Aug 2020

Cited by 11 | Viewed by 2840

Abstract

The health of peri-implant soft tissues is important for the long-term success rate of dental implants and the surface topography is pivotal in influencing it. Thus, the aim of this study was to evaluate, in human patients, the inflammatory mucosal microenvironment in the [...] Read more.

The health of peri-implant soft tissues is important for the long-term success rate of dental implants and the surface topography is pivotal in influencing it. Thus, the aim of this study was to evaluate, in human patients, the inflammatory mucosal microenvironment in the tissue surrounding a new, nanoscale, laser-treated healing abutment characterized by engineered nanopores versus a standard machined-surface. Analyses of anti- and pro-inflammatory markers, cytokeratins, desmosomal proteins and scanning electron microscopy were performed in 30 soft-tissue biopsies retrieved during second-stage surgery. The results demonstrate that the soft tissue surrounding the laser-treated surface was characterized by a lower grade of inflammation than the one facing the machined-surface, which, in turn, showed a disrupted epithelium and altered desmosomes. Moreover, higher adhesion of the epithelial cells on the laser-treated surface was detected compared to the machined one. In conclusion, the laser-treated surface topography seems to play an important role not only in cell adhesion, but also on the inflammatory makers’ expression of the soft tissue microenvironment. Thus, from a clinical point of view, the use of this kind of topography may be of crucial importance not only on healing abutments but also on prosthetic ones. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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16 pages, 1901 KiB

Open AccessArticle

In Vitro Determination of the Immunogenic Impact of Nanomaterials on Primary Peripheral Blood Mononuclear Cells

by Christopher A. W. David, Michael Barrow, Patricia Murray, Matthew J. Rosseinsky, Andrew Owen and Neill J. Liptrott

Int. J. Mol. Sci. 2020, 21(16), 5610; https://doi.org/10.3390/ijms21165610 - 5 Aug 2020

Cited by 7 | Viewed by 2794

Abstract

Investigation of the potential for nanomaterials to generate immunogenic effects is a key aspect of a robust preclinical evaluation. In combination with physicochemical characterization, such assessments also provide context for how material attributes influence biological outcomes. Furthermore, appropriate models for these assessments allow [...] Read more.

Investigation of the potential for nanomaterials to generate immunogenic effects is a key aspect of a robust preclinical evaluation. In combination with physicochemical characterization, such assessments also provide context for how material attributes influence biological outcomes. Furthermore, appropriate models for these assessments allow accurate in vitro to in vivo extrapolation, which is vital for the mechanistic understanding of nanomaterial action. Here we have assessed the immunogenic impact of a small panel of commercially available and in-house prepared nanomaterials on primary human peripheral blood mononuclear cells (PBMCs). A diethylaminoethyl-dextran (DEAE-dex) functionalized superparamagnetic iron oxide nanoparticle (SPION) generated detectable quantities of tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and IL-10, the only tested material to do so. The human leukemia monocytic cell line THP-1 was used to assess the potential for the nanomaterial panel to affect cellular oxidation-reduction (REDOX) via measurement of reactive oxygen species and reduced glutathione. Negatively charged sulfonate-functionalized polystyrene nanoparticles demonstrated a size-related trend for the inhibition of caspase-1, which was not observed for amine-functionalized polystyrene of similar sizes. Silica nanoparticles (310 nm) resulted in a 93% increase in proliferation compared to the untreated control (p < 0.01). No other nanomaterial treatments resulted in significant change from that of unstimulated PBMCs. Responses to the nanomaterials in the assays described demonstrate the utility of primary cells as ex vivo models for nanomaterial biological impact. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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20 pages, 3544 KiB

Open AccessArticle

An In Vitro Lung System to Assess the Proinflammatory Hazard of Carbon Nanotube Aerosols

by Hana Barosova, Bedia Begum Karakocak, Dedy Septiadi, Alke Petri-Fink, Vicki Stone and Barbara Rothen-Rutishauser

Int. J. Mol. Sci. 2020, 21(15), 5335; https://doi.org/10.3390/ijms21155335 - 27 Jul 2020

Cited by 33 | Viewed by 4108

Abstract

In vitro three-dimensional (3D) lung cell models have been thoroughly investigated in recent years and provide a reliable tool to assess the hazard associated with nanomaterials (NMs) released into the air. In this study, a 3D lung co-culture model was optimized to assess [...] Read more.

In vitro three-dimensional (3D) lung cell models have been thoroughly investigated in recent years and provide a reliable tool to assess the hazard associated with nanomaterials (NMs) released into the air. In this study, a 3D lung co-culture model was optimized to assess the hazard potential of multiwalled carbon nanotubes (MWCNTs), which is known to provoke inflammation and fibrosis, critical adverse outcomes linked to acute and prolonged NM exposure. The lung co-cultures were exposed to MWCNTs at the air-liquid interface (ALI) using the VITROCELL^® Cloud system while considering realistic occupational exposure doses. The co-culture model was composed of three human cell lines: alveolar epithelial cells (A549), fibroblasts (MRC-5), and macrophages (differentiated THP-1). The model was exposed to two types of MWCNTs (Mitsui-7 and Nanocyl) at different concentrations (2–10 μg/cm²) to assess the proinflammatory as well as the profibrotic responses after acute (24 h, one exposure) and prolonged (96 h, repeated exposures) exposure cycles. The results showed that acute or prolonged exposure to different concentrations of the tested MWCNTs did not induce cytotoxicity or apparent profibrotic response; however, suggested the onset of proinflammatory response. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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15 pages, 3672 KiB

Open AccessArticle

Modulation of the In Vivo Inflammatory Response by Pro- Versus Anti-Inflammatory Intervertebral Disc Treatments

by Carla Cunha, Graciosa Q. Teixeira, Cláudia Ribeiro-Machado, Catarina L. Pereira, Joana R. Ferreira, Maria Molinos, Susana G. Santos, Mário A. Barbosa and Raquel M. Goncalves

Int. J. Mol. Sci. 2020, 21(5), 1730; https://doi.org/10.3390/ijms21051730 - 3 Mar 2020

Cited by 16 | Viewed by 3474

Abstract

Inflammation is central in intervertebral disc (IVD) degeneration/regeneration mechanisms, and its balance is crucial to maintain tissue homeostasis. This work investigates the modulation of local and systemic inflammatory response associated with IVD degeneration/herniation by administration of PRO- versus ANTI-inflammatory treatments. Chitosan/poly-γ-glutamic acid nanocomplexes, [...] Read more.

Inflammation is central in intervertebral disc (IVD) degeneration/regeneration mechanisms, and its balance is crucial to maintain tissue homeostasis. This work investigates the modulation of local and systemic inflammatory response associated with IVD degeneration/herniation by administration of PRO- versus ANTI-inflammatory treatments. Chitosan/poly-γ-glutamic acid nanocomplexes, known as pro-inflammatory (PRO), and soluble diclofenac, a non-steroidal anti-inflammatory drug (ANTI), were intradiscally administered in a rat IVD injury model, 24 h after lesion. Two weeks after administration, a reduction of disc height accompanied by hernia formation was observed. In the PRO-inflammatory treated group, IL-1β, IL-6 and COX-2 IVD gene expression were upregulated, and loss of nucleus pulposus (NP) structure and composition was observed. Systemically, lower T-cell frequency was observed in the lymph nodes (LN) and spleen (SP) of the PRO group, together with an increase in CD4+ T cells subset in the blood (BL) and LN. In contrast, the ANTI-group had higher proteoglycans/collagen ratio and collagen type 2 content in the NP, while an increase in the frequency of myeloid cells, M1 macrophages and activated macrophages (MHCII+) was observed at the systemic level. Overall, this study illustrates the dynamics of local and systemic inflammatory and immune cell responses associated with intradiscal therapies, which will contribute to designing more successful immunomodulatory treatments for IVD degeneration. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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Review

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26 pages, 2016 KiB

Open AccessReview

Nanomaterials and Their Impact on the Immune System

by Alaa A. Aljabali, Mohammad A. Obeid, Rasha M. Bashatwah, Ángel Serrano-Aroca, Vijay Mishra, Yachana Mishra, Mohamed El-Tanani, Altijana Hromić-Jahjefendić, Deepak N. Kapoor, Rohit Goyal, Gowhar A. Naikoo and Murtaza M. Tambuwala

Int. J. Mol. Sci. 2023, 24(3), 2008; https://doi.org/10.3390/ijms24032008 - 19 Jan 2023

Cited by 26 | Viewed by 5479

Abstract

Nanomaterials have been the focus of intensive development and research in the medical and industrial sectors over the past several decades. Some studies have found that these compounds can have a detrimental impact on living organisms, including their cellular components. Despite the obvious [...] Read more.

Nanomaterials have been the focus of intensive development and research in the medical and industrial sectors over the past several decades. Some studies have found that these compounds can have a detrimental impact on living organisms, including their cellular components. Despite the obvious advantages of using nanomaterials in a wide range of applications, there is sometimes skepticism caused by the lack of substantial proof that evaluates potential toxicities. The interactions of nanoparticles (NPs) with cells of the immune system and their biomolecule pathways are an area of interest for researchers. It is possible to modify NPs so that they are not recognized by the immune system or so that they suppress or stimulate the immune system in a targeted manner. In this review, we look at the literature on nanomaterials for immunostimulation and immunosuppression and their impact on how changing the physicochemical features of the particles could alter their interactions with immune cells for the better or for the worse (immunotoxicity). We also look into whether the NPs have a unique or unexpected (but desired) effect on the immune system, and whether the surface grafting of polymers or surface coatings makes stealth nanomaterials that the immune system cannot find and get rid of. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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74 pages, 1761 KiB

Open AccessReview

Nanoparticle Effects on Stress Response Pathways and Nanoparticle–Protein Interactions

by Shana J. Cameron, Jessica Sheng, Farah Hosseinian and William G. Willmore

Int. J. Mol. Sci. 2022, 23(14), 7962; https://doi.org/10.3390/ijms23147962 - 19 Jul 2022

Cited by 23 | Viewed by 4554

Abstract

Nanoparticles (NPs) are increasingly used in a wide variety of applications and products; however, NPs may affect stress response pathways and interact with proteins in biological systems. This review article will provide an overview of the beneficial and detrimental effects of NPs on [...] Read more.

Nanoparticles (NPs) are increasingly used in a wide variety of applications and products; however, NPs may affect stress response pathways and interact with proteins in biological systems. This review article will provide an overview of the beneficial and detrimental effects of NPs on stress response pathways with a focus on NP–protein interactions. Depending upon the particular NP, experimental model system, and dose and exposure conditions, the introduction of NPs may have either positive or negative effects. Cellular processes such as the development of oxidative stress, the initiation of the inflammatory response, mitochondrial function, detoxification, and alterations to signaling pathways are all affected by the introduction of NPs. In terms of tissue-specific effects, the local microenvironment can have a profound effect on whether an NP is beneficial or harmful to cells. Interactions of NPs with metal-binding proteins (zinc, copper, iron and calcium) affect both their structure and function. This review will provide insights into the current knowledge of protein-based nanotoxicology and closely examines the targets of specific NPs. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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15 pages, 3566 KiB

Open AccessReview

Nanomaterials and the Serosal Immune System in the Thoracic and Peritoneal Cavities

by C. Frieke Kuper, Raymond H. H. Pieters and Jolanda H. M. van Bilsen

Int. J. Mol. Sci. 2021, 22(5), 2610; https://doi.org/10.3390/ijms22052610 - 5 Mar 2021

Cited by 2 | Viewed by 4614

Abstract

The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to maintain local homeostasis and repair local tissue damage, and to cooperate closely with the mucosal immune [...] Read more.

The thoracic and peritoneal cavities are lined by serous membranes and are home of the serosal immune system. This immune system fuses innate and adaptive immunity, to maintain local homeostasis and repair local tissue damage, and to cooperate closely with the mucosal immune system. Innate lymphoid cells (ILCs) are found abundantly in the thoracic and peritoneal cavities, and they are crucial in first defense against pathogenic viruses and bacteria. Nanomaterials (NMs) can enter the cavities intentionally for medical purposes, or unintentionally following environmental exposure; subsequent serosal inflammation and cancer (mesothelioma) has gained significant interest. However, reports on adverse effects of NM on ILCs and other components of the serosal immune system are scarce or even lacking. As ILCs are crucial in the first defense against pathogenic viruses and bacteria, it is possible that serosal exposure to NM may lead to a reduced resistance against pathogens. Additionally, affected serosal lymphoid tissues and cells may disturb adipose tissue homeostasis. This review aims to provide insight into key effects of NM on the serosal immune system. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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Graphical abstract

35 pages, 999 KiB

Open AccessReview

Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System

by Nicolaj S. Bischoff, Theo M. de Kok, Dick T.H.M. Sijm, Simone G. van Breda, Jacco J. Briedé, Jacqueline J.M. Castenmiller, Antoon Opperhuizen, Yolanda I. Chirino, Hubert Dirven, David Gott, Eric Houdeau, Agnes G. Oomen, Morten Poulsen, Gerhard Rogler and Henk van Loveren

Int. J. Mol. Sci. 2021, 22(1), 207; https://doi.org/10.3390/ijms22010207 - 28 Dec 2020

Cited by 51 | Viewed by 8670

Abstract

Titanium dioxide (TiO₂) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO₂ [...] Read more.

Titanium dioxide (TiO₂) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO₂ and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO₂ warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO₂, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO₂ and nano-sized TiO₂ in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO₂. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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23 pages, 1191 KiB

Open AccessReview

The Impact of Nanoparticles on Innate Immune Activation by Live Bacteria

by Benjamin J. Swartzwelter, Alexandra C. Fux, Litty Johnson, Elmer Swart, Sabine Hofer, Norbert Hofstätter, Mark Geppert, Paola Italiani, Diana Boraschi, Albert Duschl and Martin Himly

Int. J. Mol. Sci. 2020, 21(24), 9695; https://doi.org/10.3390/ijms21249695 - 18 Dec 2020

Cited by 19 | Viewed by 4880

Abstract

The innate immune system evolved to detect and react against potential dangers such as bacteria, viruses, and environmental particles. The advent of modern technology has exposed innate immune cells, such as monocytes, macrophages, and dendritic cells, to a relatively novel type of particulate [...] Read more.

The innate immune system evolved to detect and react against potential dangers such as bacteria, viruses, and environmental particles. The advent of modern technology has exposed innate immune cells, such as monocytes, macrophages, and dendritic cells, to a relatively novel type of particulate matter, i.e., engineered nanoparticles. Nanoparticles are not inherently pathogenic, and yet cases have been described in which specific nanoparticle types can either induce innate/inflammatory responses or modulate the activity of activated innate cells. Many of these studies rely upon activation by agonists of toll-like receptors, such as lipopolysaccharide or peptidoglycan, instead of the more realistic stimulation by whole live organisms. In this review we examine and discuss the effects of nanoparticles on innate immune cells activated by live bacteria. We focus in particular on how nanoparticles may interfere with bacterial processes in the context of innate activation, and confine our scope to the effects due to particles themselves, rather than to molecules adsorbed on the particle surface. Finally, we examine the long-lasting consequences of coexposure to nanoparticles and bacteria, in terms of potential microbiome alterations and innate immune memory, and address nanoparticle-based vaccine strategies against bacterial infection. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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29 pages, 731 KiB

Open AccessReview

Susceptibility Factors in Chronic Lung Inflammatory Responses to Engineered Nanomaterials

by Dorothy J. You and James C. Bonner

Int. J. Mol. Sci. 2020, 21(19), 7310; https://doi.org/10.3390/ijms21197310 - 3 Oct 2020

Cited by 13 | Viewed by 5094

Abstract

Engineered nanomaterials (ENMs) are products of the emerging nanotechnology industry and many different types of ENMs have been shown to cause chronic inflammation in the lungs of rodents after inhalation exposure, suggesting a risk to human health. Due to the increasing demand and [...] Read more.

Engineered nanomaterials (ENMs) are products of the emerging nanotechnology industry and many different types of ENMs have been shown to cause chronic inflammation in the lungs of rodents after inhalation exposure, suggesting a risk to human health. Due to the increasing demand and use of ENMs in a variety of products, a careful evaluation of the risks to human health is urgently needed. An assessment of the immunotoxicity of ENMs should consider susceptibility factors including sex, pre-existing diseases, deficiency of specific genes encoding proteins involved in the innate or adaptive immune response, and co-exposures to other chemicals. This review will address evidence from experimental animal models that highlights some important issues of susceptibility to chronic lung inflammation and systemic immune dysfunction after pulmonary exposure to ENMs. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System)

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Other

Jump to: Research, Review

13 pages, 937 KiB

Open AccessPerspective

Association between Microorganisms and Microplastics: How Does It Change the Host–Pathogen Interaction and Subsequent Immune Response?

by Wenjie Yang, Yang Li and Diana Boraschi

Int. J. Mol. Sci. 2023, 24(4), 4065; https://doi.org/10.3390/ijms24044065 - 17 Feb 2023

Cited by 12 | Viewed by 3312

Abstract

Plastic pollution is a significant problem worldwide because of the risks it poses to the equilibrium and health of the environment as well as to human beings. Discarded plastic released into the environment can degrade into microplastics (MPs) due to various factors, such [...] Read more.

Plastic pollution is a significant problem worldwide because of the risks it poses to the equilibrium and health of the environment as well as to human beings. Discarded plastic released into the environment can degrade into microplastics (MPs) due to various factors, such as sunlight, seawater flow, and temperature. MP surfaces can act as solid scaffolds for microorganisms, viruses, and various biomolecules (such as LPS, allergens, and antibiotics), depending on the MP characteristics of size/surface area, chemical composition, and surface charge. The immune system has efficient recognition and elimination mechanisms for pathogens, foreign agents, and anomalous molecules, including pattern recognition receptors and phagocytosis. However, associations with MPs can modify the physical, structural, and functional characteristics of microbes and biomolecules, thereby changing their interactions with the host immune system (in particular with innate immune cells) and, most likely, the features of the subsequent innate/inflammatory response. Thus, exploring differences in the immune response to microbial agents that have been modified by interactions with MPs is meaningful in terms of identifying new possible risks to human health posed by anomalous stimulation of immune reactivities. Full article

(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)

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