High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages
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ABSTRACT:
SUBMITTER: Mo Y
PROVIDER: S-EPMC10621103 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:AimsAccumulating evidence has suggested that airborne fine particulate matter (PM2.5) exposure is associated with an increased risk of ischemic stroke. However, the underlying mechanisms have not been fully elucidated. In this study, we aim to investigate the role and mechanisms of NLRP3 inflammasome and pyroptosis in ischemic stroke after PM2.5 exposure.MethodsThe BV-2 and HMC-3 microglial cell lines were established and subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) with or without PM2.5 exposure. We used the CCK-8 assay to explore the effects of PM2.5 on cell viability of BV-2 and HMC-3 cells. Then, the effects of PM2.5 exposure on NLRP3 inflammasome and pyroptosis following OGD/R were detected by western blotting, ELISA, and the confocal immunofluorescence staining. Afterwards, NLRP3 was knocked down to further validate the effects of PM2.5 on cell viability, NLRP3 inflammasome activation, and pyroptosis after OGD/R in HMC-3 cells. Finally, the intracellular reactive oxygen species (ROS) was measured and the ROS inhibitor N-acetyl-L-cysteine (NAC) was used to investigate whether ROS was required for PM2.5-induced NLRP3 inflammasome activation and pyroptosis under ischemic conditions.ResultsWe found that PM2.5 exposure decreased the viability of BV-2 and HMC-3 cells in a dose- and time-dependent manner under ischemic conditions. Furthermore, PM2.5 exposure aggravated NLRP3 inflammasome activation and pyroptosis after OGD/R, as indicated by an increased expression of NLRP3, ASC, pro-caspase-1, Caspase-1, GSDMD, and GSDMD-N; increased production of IL-1β and IL-18; and enhanced Caspase-1 activity and SYTOX green uptake. However, shRNA NLRP3 treatment attenuated the effects of PM2.5 on cell viability, NLRP3 inflammasome activation, and pyroptosis. Moreover, we observed that PM2.5 exposure increased the production of intracellular ROS following OGD/R, while inhibiting ROS production with NAC partially attenuated PM2.5-induced NLRP3 inflammasome activation and pyroptosis under ischemic conditions.ConclusionThese results suggested that PM2.5 exposure triggered the activation of NLRP3 inflammasome and pyroptosis under ischemic conditions, which may be mediated by increased ROS production after ischemic stroke. These findings may provide a more enhanced understanding of the interplay between PM2.5 and neuroinflammation and cell death, and reveal a novel mechanism of PM2.5-mediated toxic effects after ischemic stroke.
| S-EPMC9160454 | biostudies-literature
Project description:Exposure to air pollution fine particulate matter (PM2.5) aggravates respiratory and cardiovascular diseases. It has been proposed that PM2.5 uptake by alveolar macrophages promotes local inflammation that ignites a systemic response, but precise underlying mechanisms remain unclear. Here, we demonstrate that PM2.5 phagocytosis leads to NLRP3 inflammasome activation and subsequent release of the pro-inflammatory master cytokine IL-1β. Inflammasome priming and assembly was time- and dose-dependent in inflammasome-reporter THP-1-ASC-GFP cells, and consistent across PM2.5 samples of variable chemical composition. While inflammasome activation was promoted by different PM2.5 surrogates, significant IL-1β release could only be observed after stimulation with transition-metal rich Residual Oil Fly Ash (ROFA) particles. This effect was confirmed in primary human monocyte-derived macrophages and murine bone marrow-derived macrophages (BMDMs), and by confocal imaging of inflammasome-reporter ASC-Citrine BMDMs. IL-1β release by ROFA was dependent on the NLRP3 inflammasome, as indicated by lack of IL-1β production in ROFA-exposed NLRP3-deficient (Nlrp3-/-) BMDMs, and by specific NLRP3 inhibition with the pharmacological compound MCC950. In addition, while ROFA promoted the upregulation of pro-inflammatory gene expression and cytokines release, MCC950 reduced TNF-α, IL-6, and CCL2 production. Furthermore, inhibition of TNF-α with a neutralizing antibody decreased IL-1β release in ROFA-exposed BMDMs. Using electron tomography, ROFA particles were observed inside intracellular vesicles and mitochondria, which showed signs of ultrastructural damage. Mechanistically, we identified lysosomal rupture, K+ efflux, and impaired mitochondrial function as important prerequisites for ROFA-mediated IL-1β release. Interestingly, specific inhibition of superoxide anion production (O2•-) from mitochondrial respiratory Complex I, but not III, blunted IL-1β release in ROFA-exposed BMDMs. Our findings unravel the mechanism by which PM2.5 promotes IL-1β release in macrophages and provide a novel link between innate immune response and exposure to air pollution PM2.5.
| S-EPMC10804998 | biostudies-literature
Project description:Short-term elevations in fine particulate matter air pollution (PM2.5) are associated with increased risk of acute cerebrovascular events. Evidence from the peripheral circulation suggests that vascular dysfunction may be a central mechanism. However, the effects of PM2.5 on cerebrovascular function and hemodynamics are unknown.We used transcranial Doppler ultrasound to measure beat-to-beat blood flow velocity in the middle cerebral artery at rest and in response to changes in end-tidal CO2 (cerebral vasoreactivity) and arterial blood pressure (cerebral autoregulation) in 482 participants from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) of Boston study. We used linear mixed effects models with random subject intercepts to evaluate the association between cerebrovascular hemodynamic parameters and mean PM2.5 levels 1 to 28 days earlier adjusting for age, race, medical history, meteorologic covariates, day of week, temporal trends, and season.An interquartile range increase (3.0 µg/m(3)) in mean PM2.5 levels during the previous 28 days was associated with an 8.6% (95% confidence interval, 3.7%-13.8%; P<0.001) higher cerebral vascular resistance and a 7.5% (95% confidence interval, 4.2%-10.6%; P<0.001) lower blood flow velocity at rest. Measures of cerebral vasoreactivity and autoregulation were not associated with PM2.5 levels.In this cohort of community-dwelling seniors, exposure to PM2.5 was associated with higher resting cerebrovascular resistance and lower cerebral blood flow velocity. If replicated, these findings suggest that alterations in cerebrovascular hemodynamics may underlie the increased risk of particle-related acute cerebrovascular events.
| S-EPMC3722046 | biostudies-literature
Project description:Pathogenic microorganisms are sensed by the inflammasome, resulting in the release of the pro-immune and proinflammatory cytokine interleukin-1β (IL-1β). In humans, the paired sialic acid-binding Ig-like lectin receptors Siglec-5 (inhibitory) and Siglec-14 (activating) have been shown to have reciprocal roles in regulating macrophage immune responses, but their interaction with IL-1β signaling and the inflammasome has not been characterized. Here we show that in response to known inflammasome activators (ATP, nigericin) or the sialic acid-expressing human bacterial pathogen group B Streptococcus (GBS), the presence of Siglec-14 enhances, whereas Siglec-5 reduces, inflammasome activation and macrophage IL-1β release. Human THP-1 macrophages stably transfected with Siglec-14 exhibited increased caspase-1 activation, IL-1β release and pyroptosis after GBS infection, in a manner blocked by a specific inhibitor of nucleotide-binding domain leucine-rich repeat protein 3 (NLRP3), a protein involved in inflammasome assembly. Another leading pathogen, Streptococcus pneumoniae, lacks sialic acid but rather prominently expresses a sialidase, which cleaves sialic acid from macrophages, eliminating cis- interactions with the lectin receptor, thus attenuating Siglec-14 induced IL-1β secretion. Vimentin, a cytoskeletal protein released during macrophage inflammatory activation is known to induce the inflammasome. We found that vimentin has increased interaction with Siglec-14 compared to Siglec-5, and this interaction heightened IL-1β production by Siglec-14-expressing cells. Siglec-14 is absent from some humans because of a SIGLEC5/14 fusion polymorphism, and we found increased IL-1β expression in primary macrophages from SIGLEC14+/+ individuals compared to those with the SIGLEC14-/+ and SIGLEC14-/- genotypes. Collectively, our results identify a new immunoregulatory role of Siglec-14 as a positive regulator of NLRP3 inflammasome activation.
| S-EPMC7383293 | biostudies-literature
Project description:BackgroundEpidemiological observations have demonstrated that ambient fine particulate matter with dp < 2.5 μm (PM2.5) as the major factor responsible for the increasing incidence of lung cancer in never-smokers. However, there are very limited experimental data to support the association of PM2.5 with lung carcinogenesis and to compare PM2.5 with smoking carcinogens.MethodsTo study whether PM2.5 can contribute to lung tumorigenesis in a way similar to smoking carcinogen 4-methylnitrosamino-l-3-pyridyl-butanone (NNK) via 15-lipoxygenases (15-LOXs) reduction, normal lung epithelial cells and cancer cells were treated with NNK or PM2.5 and then epigenetically and post-translationally examined the cellular and molecular profiles of the cells. The data were verified in lung cancer samples and a mouse lung tumor model.ResultsWe found that similar to smoking carcinogen NNK, PM2.5 significantly enhanced cell proliferation, migration and invasion, but reduced the levels of 15-lipoxygenases-1 (15-LOX1) and 15-lipoxygenases-2 (15-LOX2), both of which were also obviously decreased in lung cancer tissues. 15-LOX1/15-LOX2 overexpression inhibited the oncogenic cell functions induced by PM2.5/NNK. The tumor formation and growth were significantly higher/faster in mice implanted with PM2.5- or NNK-treated NCI-H23 cells, accompanied with a reduction of 15-LOX1/15-LOX2. Moreover, 15-LOX1 expression was epigenetically regulated at methylation level by PM2.5/NNK, while both 15-LOX1 and 15-LOX2 could be significantly inhibited by a set of PM2.5/NNK-mediated microRNAs.ConclusionCollectively, PM2.5 can function as the smoking carcinogen NNK to induce lung tumorigenesis by inhibiting 15-LOX1/15-LOX2.
| S-EPMC6697918 | biostudies-literature
Project description:Epidemiologic and health impact studies are inhibited by the paucity of global, long-term measurements of the chemical composition of fine particulate matter. We inferred PM2.5 chemical composition at 0.1° × 0.1° spatial resolution for 2004-2008 by combining aerosol optical depth retrieved from the MODIS and MISR satellite instruments, with coincident profile and composition information from the GEOS-Chem global chemical transport model. Evaluation of the satellite-model PM2.5 composition data set with North American in situ measurements indicated significant spatial agreement for secondary inorganic aerosol, particulate organic mass, black carbon, mineral dust, and sea salt. We found that global population-weighted PM2.5 concentrations were dominated by particulate organic mass (11.9 ± 7.3 ?g/m(3)), secondary inorganic aerosol (11.1 ± 5.0 ?g/m(3)), and mineral dust (11.1 ± 7.9 ?g/m(3)). Secondary inorganic PM2.5 concentrations exceeded 30 ?g/m(3) over East China. Sensitivity simulations suggested that population-weighted ambient PM2.5 from biofuel burning (11 ?g/m(3)) could be almost as large as from fossil fuel combustion sources (17 ?g/m(3)). These estimates offer information about global population exposure to the chemical components and sources of PM2.5.
| S-EPMC4238642 | biostudies-literature
Project description:Ambient air pollution and temperature have been linked with cardiovascular morbidity and mortality. Metabolic syndrome and its components-abdominal obesity, elevated fasting blood glucose concentration, low high-density lipoprotein cholesterol concentration, hypertension, and hypertriglyceridemia-predict cardiovascular disease, but the environmental causes are understudied. In this study, we prospectively examined the long-term associations of air pollution, defined as particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5), and temperature with the development of metabolic syndrome and its components. Using covariate-adjustment Cox proportional hazards models, we estimated associations of mean annual PM2.5 concentration and temperature with risk of incident metabolic dysfunctions between 1993 and 2011 in 587 elderly (mean = 70 (standard deviation, 7) years of age) male participants in the Normative Aging Study. A 1-μg/m3 increase in mean annual PM2.5 concentration was associated with a higher risk of developing metabolic syndrome (hazard ratio (HR) = 1.27, 95% confidence interval (CI): 1.06, 1.52), an elevated fasting blood glucose level (HR = 1.20, 95% CI: 1.03, 1.39), and hypertriglyceridemia (HR = 1.14, 95% CI: 1.00, 1.30). Our findings for metabolic syndrome and high fasting blood glucose remained significant for PM2.5 levels below the Environmental Protection Agency's health-safety limit (12 μg/m3). A 1°C increase in mean annual temperature was associated with a higher risk of developing elevated fasting blood glucose (HR = 1.33, 95% CI: 1.14, 1.56). Men living in neighborhoods with worse air quality-with higher PM2.5 levels and/or temperatures than average-showed increased risk of developing metabolic dysfunctions.
| S-EPMC5209587 | biostudies-literature
Project description:Human exposure to airborne particulate matter (PM) is associated with adverse cardiopulmonary health effects, including lung cancer. Ambient PM represents a heterogeneous mixture of chemical classes including transition metals, polycyclic aromatic hydrocarbons (PAHs) and their derivatives such as nitro-PAHs, many of which are classified as putative carcinogens. As the primary site of human exposure to PM is the lungs, we investigated the response of two alveolar epithelial cell lines, the tumour-derived A549 and newly described TT1 cells, to fine and coarse PM collected from background and roadside locations. We show that coarse PM elicits a genotoxic response in the TT1 cells, with the strongest signal associated with the background sample. This response could be recapitulated using the organic extract derived from this sample. No responses were observed in PM-challenged A549 cells. Fine PM failed to elicit a genotoxic response in either cell line despite the higher PAH concentrations within this fraction. Consistent with the lack of a simplistic association between PM PAH content and the observed genotoxic response, TT1 cells treated with benzo[a]pyrene (BaP) demonstrated no increase in the selected markers. In contrast, a pattern of response was observed in TT1 cells challenged with 3-nitrobenzanthrone (3-NBA) similar to that with coarse PM. Together, these data illustrated the suitability of the TT1 cell line for assessing PM-induced genotoxicity and challenge the contention that fine roadside PM poses the higher cancer risk. Furthermore, the response to 3-NBA and not BaP suggests a major contribution of nitro-PAHs to the overall toxicity of PM. Environ. Mol. Mutagen. 59:290-301, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.
| S-EPMC5947684 | biostudies-literature
Project description:Fasting blood glucose level is the primary indicator for the diagnosis of diabetes. We aim to conduct a longitudinal study on the association between long-term fine particulate matter (PM2.5) exposure and fasting blood glucose concentrations. We recruited and followed up 1449 participants older than 65 years of age in 2009, 2012, 2014, and 2017 in eight counties in China. Fasting blood glucose was repeatedly measured 3697 times in total among these participants. Data on annual ground-level PM2.5 concentrations with a 0.01° spatial resolution from 2005 to 2016 were used to assess exposures. An increase of 10 μg/m3 in 3-year average exposure to PM2.5 was associated with an increase of 0.146 mmol/L (95% confidence interval [CI]: 0.045, 0.248) in fasting blood glucose in all participants. The association was more pronounced among the subgroup with diabetes compared to the subgroup without diabetes (P < .05). In conclusion, Long-term PM2.5 exposure was associated with an increase in fasting blood glucose levels among elderly people. Elderly individuals with diabetes are particularly vulnerable to high level exposures of PM2.5. SUMMARY: Long-term PM2.5 exposure was associated with an increase in fasting blood glucose levels among elderly people. Elderly individuals with diabetes are particularly vulnerable to high level exposures of PM2.5.
| S-EPMC7183512 | biostudies-literature
Project description:Background and objectiveInhaled particulate matter (PM) causes lung inflammation and epithelial dysfunction. However, the direct effect of PM on alveolar epithelial barrier integrity is not well understood. Our aim is to determine whether PM exposure affects the alveolar epithelial cells (AEC) transepithelial electrical conductance (Gt) and tight junction (TJ) proteins.MethodsHuman AEC (A549) and primary rat AEC were exposed to PM of <10 µm in size (PM(10) ) and diesel exhaust particles (DEP), using titanium dioxide (TiO(2) ) as a control for particle size effects. Gt and permeability to fluorescein isothiocyanate-dextran (FITC-Dextran) were measured to assess barrier integrity. TJ integrity was evaluated by analysing penetration of Lanthanum nitrate (La(3+) ) under transmission electron microscopy. Surface proteins were labelled with biotin and analysed by western blot. Immunofluorescence was performed to assess colocalization of TJ proteins including occludin and zonula occludens-1 (ZO-1). PM induced dissociation of occludin-ZO-1 was evaluated by co-immunoprecipitation.ResultsPM(10) and DEP increased Gt and disrupted TJ after 3 h of treatment. PM(10) and DEP induced occludin internalization from the plasma membrane into endosomal compartments and dissociation of occludin from ZO-1. Overexpression of antioxidant enzymes manganese superoxide dismutase (MnSOD) and catalase, prevented PM-induced Gt increase, occludin reduction from the plasma membrane and its dissociation from ZO-1.ConclusionsPM induces alveolar epithelial dysfunction in part via occludin reduction at the plasma membrane and ZO-1 dissociation in AEC. Furthermore, these effects are prevented by overexpression of two different antioxidant enzymes.
| S-EPMC3625061 | biostudies-literature