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Inflammation is one of the vital mechanisms through which the immune system responds to harmful stimuli. During inflammation, proinflammatory and anti-inflammatory cytokines interplay to orchestrate fine-tuned and dynamic immune responses. The cytokine interplay governs switches in the inflammatory response and dictates the propagation and development of the inflammatory response. Molecular pathways underlying the interplay are complex, and time-resolved monitoring of mediators and cytokines is necessary as a basis to study them in detail. Our understanding can be advanced by mathematical models that enable to analyze the system of interactions and their dynamical interplay in detail. We, therefore, used a mathematical modeling approach to study the interplay between prominent proinflammatory and anti-inflammatory cytokines with a focus on tumor necrosis factor and interleukin 10 (IL-10) in lipopolysaccharide-primed primary human monocytes. Relevant time-resolved data were generated by experimentally adding or blocking IL-10 at different time points. The model was successfully trained and could predict independent validation data and was further used to perform simulations to disentangle the role of IL-10 feedbacks during an acute inflammatory event. We used the insight to obtain a reduced predictive model including only the necessary IL-10-mediated feedbacks. Finally, the validated reduced model was used to predict early IL-10-tumor necrosis factor switches in the inflammatory response. Overall, we gained detailed insights into fine-tuning of inflammatory responses in human monocytes and present a model for further use in studying the complex and dynamic process of cytokine-regulated acute inflammation.
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BACKGROUND: The inflammatory responses are central components of diseases associated with particulate matter (PM) exposure, including systemic diseases such as cardiovascular diseases (CVDs). The aim of this study was to determine if exposure to PM, including respirable dust or quartz in the iron foundry environment mediates systemic inflammatory responses, focusing on the NLRP3 inflammasome and novel or established inflammatory markers of CVDs. METHODS: The exposure to PM, including respirable dust, metals and quartz were determined in 40 foundry workers at two separate occasions per worker. In addition, blood samples were collected both pre-shift and post-shift and quantified for inflammatory markers. The respirable dust and quartz exposures were correlated to levels of inflammatory markers in blood using Pearson, Kendall τ and mixed model statistics. Analyzed inflammatory markers included: 1) general markers of inflammation, including interleukins, chemokines, acute phase proteins, and white blood cell counts, 2) novel or established inflammatory markers of CVD, such as growth/differentiation factor-15 (GDF-15), CD40 ligand, soluble suppressor of tumorigenesis 2 (sST2), intercellular/vascular adhesion molecule-1 (ICAM-1, VCAM-1), and myeloperoxidase (MPO), and 3) NLRP3 inflammasome-related markers, including interleukin (IL)-1ß, IL-18, IL-1 receptor antagonist (IL-1Ra), and caspase-1 activity. RESULTS: The average respirator adjusted exposure level to respirable dust and quartz for the 40 foundry workers included in the study was 0.65 and 0.020 mg/m3, respectively. Respirable quartz exposure correlated with several NLRP3 inflammasome-related markers, including plasma levels of IL-1ß and IL-18, and several caspase-1 activity measures in monocytes, demonstrating a reverse relationship. Respirable dust exposure mainly correlated with non-inflammasome related markers like CXCL8 and sST2. CONCLUSIONS: The finding that NLRP3 inflammasome-related markers correlated with PM and quartz exposure suggest that this potent inflammatory cellular mechanism indeed is affected even at current exposure levels in Swedish iron foundries. The results highlight concerns regarding the safety of current exposure limits to respirable dust and quartz, and encourage continuous efforts to reduce exposure in dust and quartz exposed industries.
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Poluentes Ocupacionais do Ar , Doenças Cardiovasculares , Exposição Ocupacional , Humanos , Quartzo/análise , Exposição Ocupacional/análise , Interleucina-18 , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Poeira/análise , Biomarcadores , Material Particulado , Ferro , Caspases , Exposição por Inalação/análise , Poluentes Ocupacionais do Ar/análiseRESUMO
INTRODUCTION: Psychiatric disorders are common and significantly impact the quality of life. Inflammatory processes are proposed to contribute to the emergence of psychiatric disorders. In addition to inflammation, disturbances in metabolic pathways have been observed in individuals with different psychiatric disorders. A suggested key player in the interaction between inflammation and metabolism is the Nod-like receptor 3 (NLRP3) inflammasome, and NLRP3 is known to react to a number of specific metabolites. However, little is known about the interplay between these immunometabolites and the NLRP3 inflammasome in mental health disorders. AIM: To assess the interplay between immunometabolites and inflammasome function in a transdiagnostic cohort of individuals with severe mental disorders. METHODS: Mass spectrometry-based analysis of selected immunometabolites, previously known to affect inflammasome function, were performed in plasma from low-functioning individuals with severe mental disorders (n = 39) and sex and aged-matched healthy controls (n = 39) using a transdiagnostic approach. Mann Whitney U test was used to test differences in immunometabolites between psychiatric patients and controls. To assess the relationship between inflammasome parameters, disease severity, and the immunometabolites, Spearman's rank-order correlation test was used. Conditional logistic regression was used to control for potential confounding variables. Principal component analysis was performed to explore immunometabolic patterns. RESULTS: Among the selected immunometabolites (n = 9), serine, glutamine, and lactic acid were significantly higher in the patient group compared to the controls. After adjusting for confounders, the differences remained significant for all three immunometabolites. No significant correlations were found between immunometabolites and disease severity. CONCLUSION: Previous research on metabolic changes in mental disorders has not been conclusive. This study shows that severely ill patients have common metabolic perturbations. The changes in serine, glutamine, and lactic acid could constitute a direct contribution to the low-grade inflammation observed in severe psychiatric disorders.
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Inflamassomos , Transtornos Mentais , Humanos , Idoso , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Glutamina , Qualidade de Vida , Inflamação/metabolismoRESUMO
INTRODUCTION: In light of potential negative health effects of cobalt exposure, a characterization of inflammatory mechanisms in exposed individuals is warranted. The current study investigated cobalt exposure in the Swedish hard metal industry and its relationship to inflammatory markers, including NLRP3 inflammasome activation and white blood cell (WBC) counts. MATERIALS AND METHODS: Inhalable cobalt and dust exposures, and systemic cobalt levels, were determined for 72 workers in the hard metal industry and linear regression models were applied to correlate exposure to markers of inflammasome activation and WBC counts. RESULTS: Mean exposures to inhalable dust (0.11 mg/m3) and cobalt (0.0034 mg/m3) were below the Swedish occupational exposure limits, and these low exposures did not correlate with any investigated outcomes. Instead, cobalt blood levels significantly correlated with a ca 10% decrease in IL-18 plasma levels per 10 nM cobalt increase. Furthermore, pre-shift cobalt blood and/or urine levels significantly correlated with some WBC measures, including decreased neutrophil-to-lymphocyte ratio, increased lymphocyte-to-monocyte ratio, and lymphocyte counts. CONCLUSION: The low inhalable particle exposures had no impact on WBC counts and inflammasome activation. Instead, systemic cobalt levels, which also include skin exposure, demonstrated possible suppressive effects on inflammatory responses in cobalt-exposed individuals in the hard metal industry.
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Poluentes Ocupacionais do Ar , Exposição Ocupacional , Poluentes Ocupacionais do Ar/análise , Poluentes Ocupacionais do Ar/toxicidade , Ligas , Cobalto/toxicidade , Poeira/análise , Humanos , Inflamassomos , Contagem de Leucócitos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Exposição Ocupacional/análise , Exposição Ocupacional/estatística & dados numéricos , TungstênioRESUMO
BACKGROUND: Cobalt is a dermal sensitizer, and keratinocytes respond to cobalt exposure by releasing proinflammatory mediators, regulating the immune response. OBJECTIVE: To determine the effect of cobalt on the inflammasome associated cytokine- and gene expression in cultured human keratinocytes (HaCaT). Cultivation in low- or high calcium conditions model separate differentiation states of keratinocytes in the skin. METHOD: HaCaT cells in two different states of differentiation were exposed to cobalt chloride and caspase-1 activity as well as the production of IL-1ß, IL-18 and gene expression of IL1B, IL18, NLRP3, CASP1, and PYCARD was quantified. RESULTS: High cobalt chloride exposure mediated significant increase in caspase-1 activity, cytokine levels, and IL1B and NLRP3 expression with a corresponding regulatory decrease for CASP1 and PYCARD expression. No difference between high- and low calcium culturing conditions modelling differentiation states was detected. CONCLUSIONS: Our data suggest that HaCaT cells respond with inflammmasome associated activity upon cobalt exposure in a concentration-dependent manner. These mechanisms could be of importance for the understanding of the pathophysiology behind allergic sensitization to dermal cobalt exposure.
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Cobalto/farmacologia , Citocinas/genética , Inflamassomos/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , RNA Mensageiro/genética , Pele/efeitos dos fármacos , Caspase 1/genética , Caspase 1/metabolismo , Linhagem Celular , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Modelos Lineares , RNA Mensageiro/metabolismo , Pele/citologia , Pele/metabolismo , Fatores de TempoRESUMO
PURPOSE: To study the relationship between inhalation of airborne particles and cobalt in the Swedish hard metal industry and markers of inflammation and coagulation in blood. METHODS: Personal sampling of inhalable cobalt and dust were performed for subjects in two Swedish hard metal plants. Stationary measurements were used to study concentrations of inhalable, respirable, and total dust and cobalt, PM10 and PM2.5, the particle surface area and the particle number concentrations. The inflammatory markers CC16, TNF, IL-6, IL-8, IL-10, SAA and CRP, and the coagulatory markers FVIII, vWF, fibrinogen, PAI-1 and D-dimer were measured. A complete sampling was performed on the second or third day of a working week following a work-free weekend, and additional sampling was taken on the fourth or fifth day. The mixed model analysis was used, including covariates. RESULTS: The average air concentrations of inhalable dust and cobalt were 0.11 mg/m3 and 0.003 mg/m3, respectively. For some mass-based exposure measures of cobalt and total dust, statistically significant increased levels of FVIII, vWF and CC16 were found. CONCLUSIONS: The observed relationships between particle exposure and coagulatory biomarkers may indicate an increased risk of cardiovascular disease.
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Poluentes Ocupacionais do Ar/análise , Coagulação Sanguínea , Indústria Química , Cobalto/química , Inflamação/sangue , Exposição Ocupacional/análise , Tamanho da Partícula , Ligas/análise , Biomarcadores/sangue , Cobalto/análise , Humanos , Propriedades de Superfície , Suécia , Tungstênio/análiseRESUMO
Inflammasomes cleave and activate interleukin- (IL-) 1ß and IL-18 which have both shared and unique biological functions. IL-1ß is an important mediator of the acute phase response to infections and tissue damage, whereas IL-18 takes part in activation and tailoring of the adaptive immune response. While IL-1ß has served as the prototypic indicator of inflammasome activation, few studies have compared the potential differences in IL-1ß and IL-18 production during inflammasome activation. Since these cytokines partake in different immune pathways, the involvement of inflammasome activity in different conditions needs to be described beyond IL-1ß production alone. To address a potential heterogeneity in inflammasome functionality, ATP, chitosan, or silica oxide (SiO2) were used to induce NLRP3 inflammasome activation in THP-1 cells and the subsequent outcomes were quantified. Despite using doses of the inflammasome inducers yielding similar release of IL-1ß, SiO2-stimulated cells showed a lower concentration of released IL-18 compared to ATP and chitosan. Hence, the cells stimulated with SiO2 responded with a distinctly different IL-18 : IL-1ß ratio. The difference in the IL-18 : IL-1ß ratio for SiO2 was constant over different doses. While all downstream responses were strictly dependent on a functional NLRP3 inflammasome, the differences did not depend on the level of gene expression, caspase-1 activity, or pyroptosis. We suggest that the NLRP3 inflammasome response should be considered a dynamic process, which can be described by taking the ratio between IL-1ß and IL-18 into account and moving away from an on/off perspective of inflammasome activation.
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Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Trifosfato de Adenosina/metabolismo , Western Blotting , Células Cultivadas , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Humanos , Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Células THP-1RESUMO
PURPOSE: To study the association between inhalation of particulate matter or quartz in Swedish iron foundries and the effects on NLRP3 inflammasome activation. METHODS: Particle exposure measurements were performed during an eight-hour work day for 85 foundry workers at three Swedish iron foundries. Personal sampling was used for measurement of respirable quartz and dust and stationary measurements to obtain exposure measurements for inhalable dust and PM10. The NLRP3 inflammasome markers, interleukin- (IL-) 1ß and IL-18, and inhibitors IL-1 receptor antagonist (IL-1Ra) and IL-18 binding protein (IL-18BP) were measured in plasma. Inflammasome activation was measured by caspase-1 enzymatic activity in monocytes in whole blood by flow cytometry, and expression of inflammasome-related genes was quantified using real-time PCR. Multiple linear regression analysis was used to investigate associations between PM exposures and inflammatory markers. Sex, age, smoking, current infection, BMI, and single nucleotide polymorphism in the inflammasome regulating genes CARD8 (C10X) and NLRP3 (Q705K) were included as covariates. RESULTS: The average exposure levels of respirable dust and quartz were 0.85 and 0.052 mg/m3, respectively. A significant exposure-response was found for respirable dust and IL-18 and for inhalable dust and IL-1Ra. Whole blood, drawn from study participants, was stimulated ex vivo with inflammasome priming stimuli LPS or Pam3CSK4, resulting in a 47% and 49% increase in caspase-1 enzymatic activity in monocytes. This increase in caspase-1 activity was significantly attenuated in the higher exposure groups for most PM exposure measures. CONCLUSIONS: The results indicate that exposure levels of PM in the iron foundry environment can affect the NLRP3 inflammasome and systemic inflammation.
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Inflamassomos/sangue , Inflamassomos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Adulto , Proteínas Adaptadoras de Sinalização CARD/sangue , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/sangue , Caspase 1/metabolismo , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-18/sangue , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
The inflammasome is a multiprotein complex that mediates caspase-1 activation with subsequent maturation of the proinflammatory cytokines IL-1ß and IL-18. The NLRP3 inflammasome is known to be activated by Staphylococcus aureus, one of the leading causes of bacteremia worldwide. Inflammasome activation and regulation in response to bacterial infection have been found to be of importance for a balanced host immune response. However, inflammasome signaling in vivo in humans initiated by S. aureus is currently sparsely studied. This study therefore aimed to investigate NLRP3 inflammasome activity in 20 patients with S. aureus bacteremia (SAB), by repeated measurement during the first week of bacteremia, compared with controls. Caspase-1 activity was measured in monocytes and neutrophils by flow cytometry detecting FLICA (fluorescent-labeled inhibitor of caspase-1), while IL-1ß and IL-18 was measured by Luminex and ELISA, respectively. As a measure of inflammasome priming, messenger RNA (mRNA) expression of NLRP3, CASP1 (procaspase-1), and IL1B (pro-IL-1ß) was analyzed by quantitative PCR. We found induced caspase-1 activity in innate immune cells with subsequent release of IL-18 in patients during the acute phase of bacteremia, indicating activation of the inflammasome. There was substantial interindividual variation in caspase-1 activity between patients with SAB. We also found an altered inflammasome priming with low mRNA levels of NLRP3 accompanied by elevated mRNA levels of IL1B. This increased knowledge of the individual host immune response in SAB could provide support in the effort to optimize management and treatment of each individual patient.
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Caspase 1/sangue , Inflamassomos/metabolismo , Interleucina-1beta/sangue , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bacteriemia , Feminino , Humanos , Interleucina-18 , Masculino , Pessoa de Meia-IdadeAssuntos
Portador Sadio , Infecções Meningocócicas , Neisseria meningitidis , Estudantes , Humanos , Suécia/epidemiologia , Neisseria meningitidis/isolamento & purificação , Portador Sadio/epidemiologia , Portador Sadio/microbiologia , Prevalência , Infecções Meningocócicas/epidemiologia , Infecções Meningocócicas/microbiologia , Estudantes/estatística & dados numéricos , Universidades , Adulto Jovem , Masculino , Feminino , Adolescente , AdultoRESUMO
PURPOSE: To study the relationship between inhalation of airborne particles and quartz in Swedish iron foundries and markers of inflammation and coagulation in blood. METHODS: Personal sampling of respirable dust and quartz was performed for 85 subjects in three Swedish iron foundries. Stationary measurements were used to study the concentrations of respirable dust and quartz, inhalable and total dust, PM10 and PM2.5, as well as the particle surface area and the particle number concentrations. Markers of inflammation, namely interleukins (IL-1ß, IL-6, IL-8, IL-10 and IL-12), C-reactive protein, and serum amyloid A (SAA) were measured in plasma or serum, together with markers of coagulation including fibrinogen, factor VIII (FVIII), von Willebrand factor and D-dimer. Complete sampling was performed on the second or third day of a working week after a work-free weekend, and follow-up samples were collected 2 days later. A mixed model analysis was performed including sex, age, smoking, infections, blood group, sampling day and BMI as covariates. RESULTS: The average 8-h time-weighted average air concentrations of respirable dust and quartz were 0.85 mg/m3 and 0.052 mg/m3, respectively. Participants in high-exposure groups with respect to some of the measured particle types exhibited significantly elevated levels of SAA, fibrinogen and FVIII. CONCLUSIONS: These observed relationships between particle exposure and inflammatory markers may indicate an increased risk of cardiovascular disease among foundry workers with high particulate exposure.
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Poluentes Ocupacionais do Ar/análise , Poeira/análise , Exposição por Inalação/estatística & dados numéricos , Exposição Ocupacional/estatística & dados numéricos , Quartzo/análise , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Monitoramento Ambiental , Humanos , Ferro , Metalurgia , Proteína Amiloide A Sérica/metabolismo , Dióxido de Silício , SuéciaRESUMO
BACKGROUND AND OBJECTIVE: We have previously reported that N-acetylcysteine (NAC), ambroxol and azithromycin (AZM) (partially) correct the chloride efflux dysfunction in cystic fibrosis bronchial epithelial (CFBE) cells with the ΔF508 homozygous mutation in vitro. METHODS: In the present paper, we further investigated possible immunomodulatory effects of these drugs on the regulation of the innate immune system by studying the expression of the cytosolic NOD-like receptors NLRC1 and NLRC2, and interleukin (IL)-6 production in CFBE cells. RESULTS: Under basal conditions, PCR and Western Blot data indicate that the NLRC2 receptor has a reduced expression in CF cells as compared to non-CF (16HBE) cells, but that the NLRC1 expression is the same in both cell lines. AZM significantly upregulated NLRC1 and NLRC2 while NAC upregulated only NLRC2 receptor expression in CF cells. Reduced basal IL-6 production was found in CF cells as compared to non-CF cells. MDP (an NLRC2 agonist), NAC and AZM, but not Tri-DAP (an NLRC1 agonist), increased IL-6 production in CF cells, indicating that in CF cells IL-6 upregulation is independent of NLRC1, but involves the activation of NLRC2. CONCLUSION: Overall, the results indicate that NAC and AZM not only can correct the chloride efflux dysfunction but also have a weakly strengthening effect on the innate immune system.
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Acetilcisteína/farmacologia , Azitromicina/farmacologia , Fibrose Cística/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Imunidade Inata/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Brônquios/imunologia , Linhagem Celular , Humanos , Imunidade Inata/imunologia , Interleucina-6/imunologia , Proteína Adaptadora de Sinalização NOD1/imunologia , Proteína Adaptadora de Sinalização NOD2/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
Activation of the NLRP3 inflammasome and subsequent generation of interleukin 1ß is initiated in macrophages upon recognition of several stimuli. In the present work, we show that gain-of-function gene variants of inflammasome components known to predispose individuals to inflammatory disorders have a host-protective role during infection with Mycobacterium tuberculosis. By isolation of macrophages from patients and healthy blood donors with genetic variants in NLRP3 and CARD8 and subsequent infection of the cells with virulent M. tuberculosis, we show that these gene variants, combined, are associated with increased control of bacterial growth in human macrophages.
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Proteínas de Transporte/genética , Variação Genética/genética , Macrófagos/microbiologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Transporte/metabolismo , Feminino , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tuberculose/metabolismo , Tuberculose/microbiologiaRESUMO
The NLRP3 inflammasome is an intracellular multiprotein complex described to be involved in both an effective host response to infectious agents and various diseases. Investigation into the NLRP3 inflammasome has been extensive in the past two decades, and often revolves around the analysis of a few specific readouts, including ASC-speck formation, caspase-1 cleavage or activation, and cleavage and release of IL-1ß and/or IL-18. Quantification of these readouts is commonly undertaken as an endpoint analysis, where the presence of each positive outcome is assessed independently of the others. In this study, we apply time-resolved analysis of a human macrophage model (differentiated THP-1-ASC-GFP cells) to commonly accessible methods. This approach yields the additional quantifiable metrics time-resolved absolute change and acceleration, allowing comparisons between readouts. Using this methodological approach, we reveal (potential) discrepancies between inflammasome-related readouts that otherwise might go undiscovered. The study highlights the importance of time-resolved data in general and may be further extended as well as incorporated into other areas of research.
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The presence of microplastics (MPs) is increasing at a dramatic rate globally, posing risks for exposure and subsequent potential adverse effects on human health. Apart from being physical objects, MP particles contain thousands of plastic-associated chemicals (i.e., monomers, chemical additives, and non-intentionally added substances) captured within the polymer matrix. These chemicals are often migrating from MPs and can be found in various environmental matrices and human food chains; increasing the risks for exposure and health effects. In addition to the physical and chemical attributes of MPs, plastic surfaces effectively bind exogenous chemicals, including environmental pollutants (e.g., heavy metals, persistent organic pollutants). Therefore, MPs can act as vectors of environmental pollution across air, drinking water, and food, further amplifying health risks posed by MP exposure. Critically, fragmentation of plastics in the environment increases the risk for interactions with cells, increases the presence of available surfaces to leach plastic-associated chemicals, and adsorb and transfer environmental pollutants. Hence, this review proposes the so-called triple exposure nexus approach to comprehensively map existing knowledge on interconnected health effects of MP particles, plastic-associated chemicals, and environmental pollutants. Based on the available data, there is a large knowledge gap in regard to the interactions and cumulative health effects of the triple exposure nexus. Each component of the triple nexus is known to induce genotoxicity, inflammation, and endocrine disruption, but knowledge about long-term and inter-individual health effects is lacking. Furthermore, MPs are not readily excreted from organisms after ingestion and they have been found accumulated in human blood, cardiac tissue, placenta, etc. Even though the number of studies on MPs-associated health impacts is increasing rapidly, this review underscores that there is a pressing necessity to achieve an integrated assessment of MPs' effects on human health in order to address existing and future knowledge gaps.
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Exposição Ambiental , Poluentes Ambientais , Microplásticos , Plásticos , Humanos , Microplásticos/toxicidade , Microplásticos/análise , Poluentes Ambientais/análise , Plásticos/toxicidade , Poluição AmbientalRESUMO
Due to their exceptional properties and cost effectiveness, polyamides or nylons have emerged as widely used materials, revolutionizing diverse industries, including industrial 3D printing or additive manufacturing (AM). Powder-based AM technologies employ tonnes of polyamide microplastics to produce complex components every year. However, the lack of comprehensive toxicity assessment of particulate polyamides and polyamide-associated chemicals, especially in the light of the global microplastics crisis, calls for urgent action. This study investigated the physicochemical properties of polyamide-12 microplastics used in AM, and assessed a number of toxicity endpoints focusing on inflammation, immunometabolism, genotoxicity, aryl hydrocarbon receptor (AhR) activation, endocrine disruption, and cell morphology. Specifically, microplastics examination by means of field emission scanning electron microscopy revealed that work flow reuse of material created a fraction of smaller particles with an average size of 1-5 µm, a size range readily available for uptake by human cells. Moreover, chemical analysis by means of gas chromatography high-resolution mass spectrometry detected several polyamide-associated chemicals including starting material, plasticizer, thermal stabilizer/antioxidant, and migrating slip additive. Even if polyamide particles and chemicals did not induce an acute inflammatory response, repeated and prolonged exposure of human primary macrophages disclosed a steady increase in the levels of proinflammatory chemokine Interleukin-8 (IL-8/CXCL-8). Moreover, targeted metabolomics disclosed that polyamide particles modulated the kynurenine pathway and some of its key metabolites. The p53-responsive luciferase reporter gene assay showed that particles per se were able to activate p53, being indicative of a genotoxic stress. Polyamide-associated chemicals triggered moderate activation of AhR and elicited anti-androgenic activity. Finally, a high-throughput and non-targeted morphological profiling by Cell Painting assay outlined major sites of bioactivity of polyamide-associated chemicals and indicated putative mechanisms of toxicity in the cells. These findings reveal that the increasing use of polyamide microplastics may pose a potential health risk for the exposed individuals, and it merits more attention.
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Nylons , Poluentes Químicos da Água , Humanos , Microplásticos/toxicidade , Plásticos/toxicidade , Proteína Supressora de Tumor p53 , Plastificantes , Poluentes Químicos da Água/análiseRESUMO
Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1ß in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-κB (nuclear factor κB). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1ß, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P<0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.
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Aterosclerose/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Perfilação da Expressão Gênica , Inflamação/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Aterosclerose/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Quimiocina CCL2/sangue , Estudos de Coortes , Citocinas/sangue , Frequência do Gene , Genótipo , Humanos , Imunidade Inata/genética , Inflamação/sangue , Mediadores da Inflamação/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Análise de Sequência com Séries de Oligonucleotídeos , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Fatores de Risco , SuéciaRESUMO
BACKGROUND: Hibernation involves periods of severely depressed metabolism (torpor) and decreases in body temperature (Tb). Small arctic mammals (<5kg), in which Tb generally drop drastically, display leukopenia during hibernation. This raised the question of whether the decreased leukocyte counts in mammalian hibernators is due to torpor per se or is secondary to low Tb. The present study examined immune cell counts in brown bears (Ursus arctos), where torpor is only associated with shallow decreases in Tb. The results were compared across hibernator species for which immune and Tb data were available. METHODS AND RESULTS: The white blood cell counts were determined by flow cytometry in 13 bears captured in the field both during summer and winter over 2 years time. Tb dropped from 39.6±0.8 to 33.5±1.1°C during hibernation. Blood neutrophils and monocytes were lower during hibernation than during the active period (47%, p= 0.001; 43%, p=0.039, respectively), whereas no change in lymphocyte counts was detected (p=0.599). Further, combining our data and those from 10 studies on 9 hibernating species suggested that the decline in Tb explained the decrease in innate immune cells (R(2)=0.83, p<0.0001). CONCLUSIONS: Bears have fewer innate immune cells in circulation during hibernation, which may represent a suppressed innate immune system. Across species comparison suggests that, both in small and large hibernators, Tb is the main driver of immune function regulation during winter dormancy. The lack of a difference in lymphocyte counts in this context requires further investigations.
Assuntos
Temperatura Corporal/fisiologia , Hibernação/fisiologia , Imunidade Inata/fisiologia , Ursidae/sangue , Animais , Citometria de Fluxo , Hibernação/imunologia , Contagem de Leucócitos , Masculino , Monócitos/citologia , Neutrófilos/citologia , Consumo de Oxigênio/fisiologia , Estações do Ano , Ursidae/fisiologiaRESUMO
The NLRP3 inflammasome is a key regulator of inflammation that responds to a broad range of stimuli. The exact mechanism of activation has not been determined, but there is a consensus on cellular potassium efflux as a major common denominator. Once NLRP3 is activated, it forms high-order complexes together with NEK7 that trigger aggregation of ASC into specks. Typically, there is only one speck per cell, consistent with the proposal that specks form - or end up at - the centrosome. ASC polymerisation in turn triggers caspase-1 activation, leading to maturation and release of IL-1ß and pyroptosis, i.e., highly inflammatory cell death. Several gain-of-function mutations in the NLRP3 inflammasome have been suggested to induce spontaneous activation of NLRP3 and hence contribute to development and disease severity in numerous autoinflammatory and autoimmune diseases. Consequently, the NLRP3 inflammasome is of significant clinical interest, and recent attention has drastically improved our insight in the range of involved triggers and mechanisms of signal transduction. However, despite recent progress in knowledge, a clear and comprehensive overview of how these mechanisms interplay to shape the system level function is missing from the literature. Here, we provide such an overview as a resource to researchers working in or entering the field, as well as a computational model that allows for evaluating and explaining the function of the NLRP3 inflammasome system from the current molecular knowledge. We present a detailed reconstruction of the molecular network surrounding the NLRP3 inflammasome, which account for each specific reaction and the known regulatory constraints on each event as well as the mechanisms of drug action and impact of genetics when known. Furthermore, an executable model from this network reconstruction is generated with the aim to be used to explain NLRP3 activation from priming and activation to the maturation and release of IL-1ß and IL-18. Finally, we test this detailed mechanistic model against data on the effect of different modes of inhibition of NLRP3 assembly. While the exact mechanisms of NLRP3 activation remains elusive, the literature indicates that the different stimuli converge on a single activation mechanism that is additionally controlled by distinct (positive or negative) priming and licensing events through covalent modifications of the NLRP3 molecule. Taken together, we present a compilation of the literature knowledge on the molecular mechanisms on NLRP3 activation, a detailed mechanistic model of NLRP3 activation, and explore the convergence of diverse NLRP3 activation stimuli into a single input mechanism.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Inflamação , PiroptoseRESUMO
Micro- and nanoplastics (MNPs) are emerging pollutants with scarcely investigated effects on human innate immunity. If they follow a similar course of action as other, more thoroughly investigated particulates, MNPs may penetrate epithelial barriers, potentially triggering a cascade of signaling events leading to cell damage and inflammation. Inflammasomes are intracellular multiprotein complexes and stimulus-induced sensors critical for mounting inflammatory responses upon recognition of pathogen- or damage-associated molecular patterns. Among these, the NLRP3 inflammasome is the most studied in terms of activation via particulates. However, studies delineating the ability of MNPs to affect NLRP3 inflammasome activation are still rare. In this review, we address the issue of MNPs source and fate, highlight the main concepts of inflammasome activation via particulates, and explore recent advances in using inflammasome activation for assessment of MNP immunotoxicity. We also discuss the impact of co-exposure and MNP complex chemistry in potential inflammasome activation. Development of robust biological sensors is crucial in order to maximize global efforts to effectively address and mitigate risks that MNPs pose for human health.