| 1. |
- Andersson, Lena, 1965-, et al.
(författare)
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Respiratory Health and Inflammatory Markers : Exposure to Cobalt in the Swedish Hard Metal Industry
- 2020
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Ingår i: Journal of Occupational and Environmental Medicine. - : Lippincott Williams & Wilkins. - 1076-2752 .- 1536-5948. ; 62:10, s. 820-829
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study the relationship between inhalable dust and cobalt and respiratory symptoms, lung function, exhaled nitric oxide in expired air and CC16 in the Swedish hard metal industry.METHODS: Personal sampling of inhalable dust and cobalt, medical examination including blood sampling was performed for 72 workers. Exposure-response relationships was determined using logistic, linear and mixed model analysis.RESULTS: The average inhalable dust and cobalt concentrations were 0.079 and 0.0017 mg/m, respectively. Statistically significant increased serum levels of CC16 were determined when the high and low cumulative exposures for cobalt were compared. Non-significant exposure-response relationships was observed between cross-shift inhalable dust or cobalt exposures and asthma, nose dripping and bronchitis.CONCLUSIONS: Our findings suggest an exposure-response relationship between inhalable cumulative cobalt exposure and CC16 levels in blood, which may reflect an injury or a reparation process in the lungs.
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| 2. |
- Lerm, Maria, 1973-, et al.
(författare)
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Leishmania donovani requires functional Cdc42 and Rac1 to prevent phagosomal maturation
- 2006
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 74:5, s. 2613-2618
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Tidskriftsartikel (refereegranskat)abstract
- Leishmania donovani promastigotes survive inside macrophage phagosomes by inhibiting phagosomal maturation. The main surface glycoconjugate on promastigotes, lipophosphoglycan (LPG), is crucial for survival and mediates the formation of a protective shell of F-actin around the phagosome. Previous studies have demonstrated that this effect involves inhibition of protein kinase Cα. The present study shows that functional Cdc42 and Rac1 are required for the formation of F-actin around L. donovani phagosomes. Moreover, we present data showing that phagosomes containing LPG-defective L. donovani, which is unable to induce F-actin accumulation, display both elevated levels of periphagosomal F-actin and impaired phagosomal maturation in macrophages with permanently active forms of Cdc42 and Rac1. We conclude that L. donovani engages Cdc42 and Rac1 to build up a protective coat of F-actin around its phagosome to prevent phagosomal maturation. Copyright © 2006, American Society for Microbiology. All Rights Reserved.
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| 3. |
- Westberg, Håkan, 1949-, et al.
(författare)
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Inflammatory and coagulatory markers and exposure to different size fractions of particle mass, number and surface area air concentrations in Swedish iron foundries, in particular respirable quartz
- 2019
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Ingår i: International Archives of Occupational and Environmental Health. - : Springer Berlin/Heidelberg. - 0340-0131 .- 1432-1246. ; 92:8, s. 1087-1098
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Tidskriftsartikel (refereegranskat)abstract
- 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-1β, 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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| 4. |
- Ydrenius, Liselotte, et al.
(författare)
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Activation of cAMP-dependent protein kinase is necessary for actin rearrangements in human neutrophils during phagocytosis
- 2000
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Ingår i: Journal of Leukocyte Biology. - 0741-5400 .- 1938-3673. ; 67:4, s. 520-528
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG-dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity measurements of phalloidin-stained actin in neutrophils showed a reduced amount of filamentous actin (F-actin) in pseudopods and around the phagosome in cells treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount of phosphotyrosine-containing proteins was also reduced in pseudopods and around the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin reorganization during receptor-mediated phagocytosis, particularly triggered by IgG-FcR interaction. Our results support the hypothesis that active subcortical reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is less important during CR3-mediated ingestion.
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| 5. |
- Alijagic, Andi, 1992-, et al.
(författare)
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A Novel Nanosafety Approach Using Cell Painting, Metabolomics, and Lipidomics Captures the Cellular and Molecular Phenotypes Induced by the Unintentionally Formed Metal-Based (Nano)Particles
- 2023
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Additive manufacturing (AM) or industrial 3D printing uses cutting-edge technologies and materials to produce a variety of complex products. However, the effects of the unintentionally emitted AM (nano)particles (AMPs) on human cells following inhalation, require further investigations. The physicochemical characterization of the AMPs, extracted from the filter of a Laser Powder Bed Fusion (L-PBF) 3D printer of iron-based materials, disclosed their complexity, in terms of size, shape, and chemistry. Cell Painting, a high-content screening (HCS) assay, was used to detect the subtle morphological changes elicited by the AMPs at the single cell resolution. The profiling of the cell morphological phenotypes, disclosed prominent concentration-dependent effects on the cytoskeleton, mitochondria, and the membranous structures of the cell. Furthermore, lipidomics confirmed that the AMPs induced the extensive membrane remodeling in the lung epithelial and macrophage co-culture cell model. To further elucidate the biological mechanisms of action, the targeted metabolomics unveiled several inflammation-related metabolites regulating the cell response to the AMP exposure. Overall, the AMP exposure led to the internalization, oxidative stress, cytoskeleton disruption, mitochondrial activation, membrane remodeling, and metabolic reprogramming of the lung epithelial cells and macrophages. We propose the approach of integrating Cell Painting with metabolomics and lipidomics, as an advanced nanosafety methodology, increasing the ability to capture the cellular and molecular phenotypes and the relevant biological mechanisms to the (nano)particle exposure.
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| 6. |
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| 7. |
- Alijagic, Andi, 1992-, et al.
(författare)
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Characteristics and health risks of the inhalable fraction of metal additive manufacturing powders
- 2024
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Ingår i: Nano Select. - : Wiley-VCH Verlagsgesellschaft. - 2688-4011. ; 5:4
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Tidskriftsartikel (refereegranskat)abstract
- Metal additive manufacturing (AM) is gaining traction but raises worker health concerns due to micron-sized powders, including fine inhalable particles. This study explored particle and surface characteristics, electrochemical properties, metal release in artificial lysosomal fluid (ALF), and potential toxicity of virgin and sieved virgin Fe-based powders, stainless steel (316L), Fe, and two tooling steels. Virgin particles ranged in size from 1 to 100μm, while sieved particles were within the respirable size range (<5–10μm). Surface oxide composition differed from bulk composition. The Fe powder showed low corrosion resistance and high metal release due to a lack of protective surface oxide. Sieved particles of 316L, Fe, and one tooling steel released more metals into ALF than virgin particles, with the opposite was observed for the other tooling steel. Sieved particles had no notable impact on cell viability or micronuclei formation in human bronchial epithelial cells. Inflammatory response in human macrophages was generally low, except for the Fe powder and one tooling steel, which induced increased interleukin-8 (IL-8/CXCL-8) and monocyte chemoattractant protein-1 (MCP-1/CCL-2) secretion. This study underscores distinctions between virgin and sieved Fe-based powders and suggests relatively low acute toxicity.
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| 8. |
- Alijagic, Andi, 1992-, et al.
(författare)
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Immunotoxic, genotoxic, and endocrine disrupting impacts of polyamide microplastic particles and chemicals
- 2024
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 183
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 9. |
- Alijagic, Andi, 1992-, et al.
(författare)
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NLRP3 inflammasome as a sensor of micro- and nanoplastics immunotoxicity
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 10. |
- Alijagic, Andi, 1992-, et al.
(författare)
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Particle Safety Assessment in Additive Manufacturing : From Exposure Risks to Advanced Toxicology Testing.
- 2022
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Ingår i: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 4
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Forskningsöversikt (refereegranskat)abstract
- Additive manufacturing (AM) or industrial three-dimensional (3D) printing drives a new spectrum of design and production possibilities; pushing the boundaries both in the application by production of sophisticated products as well as the development of next-generation materials. AM technologies apply a diversity of feedstocks, including plastic, metallic, and ceramic particle powders with distinct size, shape, and surface chemistry. In addition, powders are often reused, which may change the particles' physicochemical properties and by that alter their toxic potential. The AM production technology commonly relies on a laser or electron beam to selectively melt or sinter particle powders. Large energy input on feedstock powders generates several byproducts, including varying amounts of virgin microparticles, nanoparticles, spatter, and volatile chemicals that are emitted in the working environment; throughout the production and processing phases. The micro and nanoscale size may enable particles to interact with and to cross biological barriers, which could, in turn, give rise to unexpected adverse outcomes, including inflammation, oxidative stress, activation of signaling pathways, genotoxicity, and carcinogenicity. Another important aspect of AM-associated risks is emission/leakage of mono- and oligomers due to polymer breakdown and high temperature transformation of chemicals from polymeric particles, both during production, use, and in vivo, including in target cells. These chemicals are potential inducers of direct toxicity, genotoxicity, and endocrine disruption. Nevertheless, understanding whether AM particle powders and their byproducts may exert adverse effects in humans is largely lacking and urges comprehensive safety assessment across the entire AM lifecycle-spanning from virgin and reused to airborne particles. Therefore, this review will detail: 1) brief overview of the AM feedstock powders, impact of reuse on particle physicochemical properties, main exposure pathways and protective measures in AM industry, 2) role of particle biological identity and key toxicological endpoints in the particle safety assessment, and 3) next-generation toxicology approaches in nanosafety for safety assessment in AM. Altogether, the proposed testing approach will enable a deeper understanding of existing and emerging particle and chemical safety challenges and provide a strategy for the development of cutting-edge methodologies for hazard identification and risk assessment in the AM industry.
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| 11. |
- Alijagic, Andi, 1992-, et al.
(författare)
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The triple exposure nexus of microplastic particles, plastic-associated chemicals, and environmental pollutants from a human health perspective
- 2024
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 188
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Forskningsöversikt (refereegranskat)abstract
- 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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| 12. |
- Andersson, Lena, 1965-, et al.
(författare)
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Inflammatory and coagulatory markers and exposure to different size fractions of particle mass, number and surface area air concentrations in the Swedish hard metal industry, in particular to cobalt
- 2021
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Ingår i: Biomarkers. - : Taylor & Francis. - 1354-750X .- 1366-5804. ; 26:6, s. 557-569
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Tidskriftsartikel (refereegranskat)abstract
- 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 concentration 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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| 13. |
- Andersson, Lena, 1965-, et al.
(författare)
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Respiratory health and inflammatory markers : Exposure to respirable dust and quartz and chemical binders in Swedish iron foundries
- 2019
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To study the relationship between respirable dust, quartz and chemical binders in Swedish iron foundries and respiratory symptoms, lung function (as forced expiratory volume FEV1 and vital capacity FVC), fraction of exhaled nitric oxide (FENO) and levels of club cell secretory protein 16 (CC16) and CRP.METHODS: Personal sampling of respirable dust and quartz was performed for 85 subjects in three Swedish iron foundries. Full shift sampling and examination were performed on the second or third day of a working week after a work free weekend, with additional sampling on the fourth or fifth day. Logistic, linear and mixed model analyses were performed including, gender, age, smoking, infections, sampling day, body mass index (BMI) and chemical binders as covariates.RESULTS: The adjusted average respirable quartz and dust concentrations were 0.038 and 0.66 mg/m3, respectively. Statistically significant increases in levels of CC16 were associated with exposure to chemical binders (p = 0.05; p = 0.01) in the regression analysis of quartz and respirable dust, respectively. Non-significant exposure-responses were identified for cumulative quartz and the symptoms asthma and breathlessness. For cumulative chemical years, non-significant exposure-response were observed for all but two symptoms. FENO also exhibited a non significant exposure-response for both quartz and respirable dust. No exposure-response was determined for FEV1 or FVC, CRP and respirable dust and quartz.CONCLUSIONS: Our findings suggest that early markers of pulmonary effect, such as increased levels of CC16 and FENO, are more strongly associated with chemical binder exposure than respirable quartz and dust in foundry environments.
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| 14. |
- Andersson, Lena, 1965-, et al.
(författare)
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Silica Exposure and Cardiovascular, Cerebrovascular, and Respiratory Morbidity in a Cohort of Male Swedish Iron Foundry Workers
- 2023
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Ingår i: Journal of Occupational and Environmental Medicine. - : Lippincott Williams & Wilkins. - 1076-2752 .- 1536-5948. ; 65:9, s. 731-739
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we present quantitative exposure-response data on silica exposure in male Swedish iron foundry workers receiving inpatient care for cardiovascular, cerebrovascular, and respiratory morbidity. The study show a significantly increased COPD risk at cumulative silica exposures that correspond to TWA silica below the Swedish OEL of 0.1 mg/m3. ObjectiveWe present quantitative exposure-response data on silica exposure in male Swedish iron foundry workers for cardiovascular, cerebrovascular, and respiratory morbidity.MethodsThis research is a cohort study of 2063 male Swedish iron foundry workers. From the Swedish National Patient Registers, data on morbidity incidence were retrieved. A historical measurement database of 1667 respirable silica exposure measurements from 10 Swedish iron foundries was used to calculate the cumulative exposure dose for each worker.ResultsIncreased morbidity risk for the whole group of foundry workers was determined for ischemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), bronchitis, and pneumonia. In addition, an increased risk for COPD at cumulative silica exposures ranging from 0.11 to 0.84 mg/m3 year is presented.ConclusionsThe study presents a significantly increased COPD risk at cumulative silica exposures below the Swedish occupational exposure limit.
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| 15. |
- Asfaw Idosa, Berhane, 1977-, et al.
(författare)
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C10X polymorphism in the CARD8 gene is associated with bacteraemia
- 2014
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Ingår i: Immunity, inflammation and disease. - West Sussex, UK : John Wiley & Sons. - 2050-4527. ; 2:1, s. 13-20
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Tidskriftsartikel (refereegranskat)abstract
- The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.
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| 16. |
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| 17. |
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| 18. |
- Asfaw Idosa, Berhane, PhD, 1977-, et al.
(författare)
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Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent
- 2019
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Ingår i: Journal of Immunology Research. - : Hindawi Publishing Corporation. - 2314-8861 .- 2314-7156.
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Tidskriftsartikel (refereegranskat)abstract
- Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent, Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1 (IL-1), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanismpriming and licensing of inflammasome activationbut there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate if N. meningitidis activates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected to N. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup C N. meningitidis (FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereas lpxA was unable to induce caspase-1 activity as well as to induce IL-1 release. While the lpxA mutant induced a priming response, measured as increased expression of NLRP3 and IL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components of N. meningitidis contribute to the priming of the inflammasome activity, LOS per se is to be considered as the central component of N. meningitidis virulence, responsible for both priming and licensing of inflammasome activation.
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| 19. |
- Baban, Bayar, 1973-, et al.
(författare)
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Altered insulin sensitivity and immune function in patients with colorectal cancer
- 2023
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Ingår i: Clinical Nutrition ESPEN. - : Elsevier. - 2405-4577. ; 58, s. 193-200
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Tidskriftsartikel (refereegranskat)abstract
- Background & aims: Insulin resistance and chronic inflammation have been reported in patients with cancer. However, many of the underlying mechanisms and associations are yet to be unveiled. We examined both the level of insulin sensitivity and markers of inflammation in patients with colorectal cancer for comparison to controls.Methods: Clinical exploratory study of patients with colorectal cancer (n = 20) and matched controls (n = 10). Insulin sensitivity was quantified using the hyperinsulinemic normoglycemic clamp and blood samples were taken for quantification of several key, both intra- and extracellular, inflammatory markers. We analysed the differences in these parameters between the two groups.Results: Patients exhibited both insulin resistance (M-value, patients median (Mdn) 4.57 interquartile range (IQR) 3.49-5.75; controls Mdn 5.79 (IQR 5.20-6.81), p = 0.049), as well as increased plasma levels of the pro-inflammatory cytokines IL-1b(patients Mdn 0.48 (IQR 0.33-0.58); controls Mdn 0.36 (IQR 0.29-0.42), p = 0.02) and IL-6 (patients Mdn 3.21 (IQR 2.31-4.93); controls Mdn 2.16 (IQR 1.50-2.65), p = 0.02). The latter is present despite an almost two to three fold decrease (p < 0.01) in caspase-1 activity, a facilitating enzyme of IL-1b production, within circulating immune cells.Conclusion: Patients with colorectal cancer displayed insulin resistance and higher levels of plasma IL-1b and IL-6, in comparison to matched healthy controls. The finding of a seemingly disconnect between inflammasome (caspase-1) activity and plasma levels of key pro-inflammatory cytokines in cancer patients may suggest that, in parallel to dysregulated immune cells, tumour-driven inflammatory pathways also are in effect.
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| 20. |
- Baban, Bayar, 1973-
(författare)
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Colorectal cancer and surgery : Insights into insulin resistance and inflammatory markers
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The art of surgery has progressively extended from the realm of anatomy to encompass physiology and beyond, in search of further refinement and optimal recovery. Integral to this is a deeper understanding of the body’s essential metabolic and inflammatory responses to surgical trauma.This thesis aims to provide insights into the intricate interplay between insulin resistance, inflammation and surgical interventions in colorectal cancer patients, as each has an influence on postoperative recovery. Particular emphasis is placed on the role of inflammasomes – central mediators of the innate immune response, adept at detecting and responding to a diverse range of triggers, yet insufficiently explored in these specific contexts.Study I is a comparative analysis of the hyperinsulinemic–euglycaemic clamp and homeostatic model assessment (HOMA) in determining postoperative insulin resistance in 113 patients undergoing various elective surgeries. The findings establish the clamp as the accurate method, detecting key physiological distinctions missed by HOMA.Study II, an exploratory case–control study, assesses insulin sensitivity and inflammatory markers in 20 colorectal cancer patients compared to 10 matched healthy controls. Results indicate insulin resistance, reduced inflammasome activity in circulating immune cells and elevated systemic IL-1β and IL-6 levels in patients.Study III, a pilot exploratory study of 17 patients from Study II, assesses the impact of surgical technique, open versus minimally invasive surgery, on postoperative insulin resistance and inflammation in colorectal cancer resections. It indicates a differential inflammatory response with higher levels in open surgeries, yet a consistent degree of insulin resistance across both surgical techniques.Study IV explores the perioperative temporal sequencing of inflammation and inflammasome action in 18 patients from Study II undergoing elective colorectal cancer resections. It points to a more immediate and pronounced inflammatory response in open surgery compared to minimally invasive surgery, though both techniques show reduced intraoperative caspase-1 activity.In conclusion, the hyperinsulinemic euglycaemic clamp is the accurate method in determinations of postoperative insulin resistance. Patients with colorectal cancer, in comparison to matched healthy controls, exhibit insulin resistance and higher levels of inflammation, but decreased inflammasome (caspase-1) activity in circulating immune cells. Finally, colorectal cancer resections induce both insulin resistance and inflammation; however, the surgical technique utilized only significantly affects the latter, with generally higher inflammatory / inflammasome responses in open surgery.
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| 21. |
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| 22. |
- Baban, Bayar, 1973-, et al.
(författare)
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Inflammasome activation, colonic cancer and glucose metabolism
- 2016
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Ingår i: Clinical Nutrition ESPEN. - : Elsevier. - 2405-4577. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To study the association between inflammasome activation (a potent initiator of inflammation acting via caspase-1 and maturation of interleukin-1β), colonic cancer and glucose metabolism.Methods: Five patients with colon cancer and ten matched controls without cancer were measured for insulin sensitivity using the hyperinsulinemic euglycemic clamp. For detection of inflammasome activation the caspase-1 activity, determined by detecting FLICA using flow cytometry, was measured in both monocytes and granulocytes at the start of, and at 120 minutes into the clamp. Descriptive and analytical statistics were performed using nonparametric methods by SPSS.Results: There was no difference in levels of insulin sensitivity between the two groups (p=0.09). The cancer patients had significantly lower levels of caspase-1 both in monocytes (p<0.05) and granulocytes (p<0.05) compared with the controls. However both patients and controls had significantly higher levels of both mono- and granulocyte caspase-1 activity at 120 minutes into the clamp as compared to at start (p<0.05). Patients showed an overall higher relative increase in caspase-1 during the clamp, however this finding did not reach statistical significance (monocytes; p=0.27, granulocytes; p=0.22).
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| 23. |
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| 24. |
- Bergström, Ida, et al.
(författare)
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Annexin A1 in blood mononuclear cells from patients with coronary artery disease : Its association with inflammatory status and glucocorticoid sensitivity
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Blood was collected from 57 patients with stable CAD (SCAD) and 41 healthy controls. We also included a minor group (n = 10) with acute coronary syndrome (ACS). AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound) and glucocorticoid receptors (GR) were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL)-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.
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| 25. |
- Blomgran, Robert, et al.
(författare)
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Common Genetic Variations in the NALP3 Inflammasome Are Associated with Delayed Apoptosis of Human Neutrophils
- 2012
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Ingår i: PLOS ONE. - San Francisco, USA : Public Library of Science. - 1932-6203. ; 7:3
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Neutrophils are key-players in the innate host defense and their programmed cell death and removal are essential for efficient resolution of inflammation. These cells recognize a variety of pathogens, and the NOD-like receptors (NLRs) have been suggested as intracellular sensors of microbial components and cell injury/stress. Some NLR will upon activation form multi-protein complexes termed inflammasomes that result in IL-1 beta production. NLR mutations are associated with auto-inflammatory syndromes, and our previous data propose NLRP3 (Q705K)/CARD-8 (C10X) polymorphisms to contribute to increased risk and severity of inflammatory disease by acting as genetic susceptibility factors. These gene products are components of the NALP3 inflammasome, and approximately 6.5% of the Swedish population are heterozygote carriers of these combined gene variants. Since patients carrying the Q705K/C10X polymorphisms display leukocytosis, the aim of the present study was to find out whether the inflammatory phenotype was related to dysfunctional apoptosis and impaired clearance of neutrophils by macrophages. less thanbrgreater than less thanbrgreater thanMethods and Findings: Patients carrying the Q705K/C10X polymorphisms displayed significantly delayed spontaneous as well as microbe-induced apoptosis compared to matched controls. Western blotting revealed increased levels and phosphorylation of Akt and Mcl-1 in the patients neutrophils. In contrast to macrophages from healthy controls, macrophages from the patients produced lower amounts of TNF; suggesting impaired macrophage clearance response. less thanbrgreater than less thanbrgreater thanConclusions: The Q705K/C10X polymorphisms are associated with delayed apoptosis of neutrophils. These findings are explained by altered involvement of different regulators of apoptosis, resulting in an anti-apoptotic profile. Moreover, the macrophage response to ingestion of microbe-induced apoptotic neutrophils is altered in the patients. Taken together, the patients display impaired turnover and clearance of apoptotic neutrophils, pointing towards a dysregulated innate immune response that influences the resolution of inflammation. The future challenge is to understand how microbes affect the activation of inflammasomes, and why this interaction will develop into severe inflammatory disease in certain individuals.
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| 26. |
- Demirel, Isak, 1987-, et al.
(författare)
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Activation of NLRP3 by uropathogenic Escherichia coli is associated with IL-1β release and regulation of antimicrobial properties in human neutrophils
- 2020
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- The NLRP3 inflammasome and IL-1β have recently been linked to the severity of uropathogenic Escherichia coli (UPEC)-mediated urinary tract infection (UTI). However, not much is known about the contribution of NLRP3 to the antimicrobial properties of neutrophils and the release of IL-1β during UPEC infection. The purpose of this study was to elucidate the mechanisms behind UPEC-induced IL-1β release from human neutrophils, and to investigate the contribution of the NLRP3 inflammasome in neutrophil-mediated inhibition of UPEC growth. We found that the UPEC strain CFT073 increased the expression of NLRP3 and increased caspase-1 activation and IL-1β release from human neutrophils. The IL-1β release was mediated by the NLRP3 inflammasome and by serine proteases in an NF-κB-and cathepsin B-dependent manner. The UPEC virulence factors α-hemolysin, type-1 fimbriae and p-fimbriae were all shown to contribute to UPEC mediated IL-1β release from neutrophils. Furthermore, inhibition of caspase-1 and NLRP3 activation increased neutrophil ROS-production, phagocytosis and the ability of neutrophils to suppress UPEC growth. In conclusion, this study demonstrates that UPEC can induce NLRP3 and serine protease-dependent release of IL-1β from human neutrophils and that NLRP3 and caspase-1 can regulate the antimicrobial activity of human neutrophils against UPEC.
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| 27. |
- Demirel, Isak, 1987-, et al.
(författare)
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Activation of the NLRP3 Inflammasome Pathway by Uropathogenic Escherichia coli Is Virulence Factor-Dependent and Influences Colonization of Bladder Epithelial Cells
- 2018
-
Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- The NLRP3 inflammasome and IL-1 beta release have recently been suggested to be important for the progression of urinary tract infection (UTI). However, much is still unknown regarding the interaction of UPEC and the NLRP3 inflammasome. The purpose of this study was to elucidate what virulence factors uropathogenic Escherichia coil (UPEC) use to modulate NLRP3 inflammasome activation and subsequent IL-1 beta release and the role of NLRP3 for UPEC colonization of bladder epithelial cells. The bladder epithelial cell line 5637, CRISPR/Cas9 generated NLRP3, caspase-1 and mesotrypsin deficient cell lines and transformed primary bladder epithelial cells (HBLAK) were stimulated with UPEC isolates and the non-pathogenic MG1655 strain. We found that the UPEC strain CFT073, but not MG1655, induced an increased caspase-1 activity and IL-1 beta release from bladder epithelial cells. The increase was shown to be mediated by et-hemolysin activation of the NLRP3 inflammasome in an NE-kappa B-independent manner. The effect of-hemolysin on IL-1 beta release was biphasic, initially suppressive, later inductive. Furthermore, the phase-locked type-1-fimbrial ON variant of CFT073 inhibited caspase-1 activation and IL-1 beta release. In addition, the ability of CFT073 to adhere to and invade NLRP3 deficient cells was significantly reduced compare to wild-type cells. The reduced colonization of NLRP3-deficient cells was type-1 fimbriae dependent. In conclusion, we found that the NLRP3 inflammasome was important for type-1 fimbriae-dependent colonization of bladder epithelial cells and that both type-1 fimbriae and alpha-hemolysin can modulate the activity of the NLRP3 inflammasome.
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| 28. |
- Eklund, Daniel, 1984-, et al.
(författare)
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Human Gene Variants Linked to Enhanced NLRP3 Activity Limit Intramacrophage Growth of Mycobacterium tuberculosis
- 2014
-
Ingår i: Journal of Infectious Diseases. - Cary, USA : Oxford University Press. - 0022-1899 .- 1537-6613. ; 209:5, s. 749-753
-
Tidskriftsartikel (refereegranskat)abstract
- Activation of the NLRP3 inflammasome and subsequent generation of interleukin 1 beta 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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| 29. |
- Forsberg, Maria, 1973-, et al.
(författare)
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Activation of Rac2 and Cdc42 on Fc and complement receptor ligation in human neutrophils
- 2003
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 74:4, s. 611-619
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Tidskriftsartikel (refereegranskat)abstract
- Phagocytosis is a complex process engaging a concerted action of signal-transduction cascades that leads to ingestion, subsequent phagolysosome fusion, and oxidative activation. We have previously shown that in human neutrophils, C3bi-mediated phagocytosis elicits a significant oxidative response, suggesting that activation of the small GTPase Rac is involved in this process. This is contradictory to macrophages, where only Fc receptor for immunoglobulin G (FcγR)-mediated activation is Rac-dependent. The present study shows that engagement of the complement receptor 3 (CR3) and FcγR and CR3- and FcγR-mediated phagocytosis activates Rac, as well as Cdc42. Furthermore, following receptor-engagement of the CR3 or FcγRs, a downstream target of these small GTPases, p21-activated kinase, becomes phosphorylated, and Rac2 is translocated to the membrane fraction. Using the methyltransferase inhibitors N-acetyl-S-farnesyl-L-cysteine and N-acetyl-S-geranylgeranyl-L-cysteine, we found that the phagocytic uptake of bacteria was not Rac2- or Cdc42-dependent, whereas the oxidative activation was decreased. In conclusion, our results indicate that in neutrophils, Rac2 and Cdc42 are involved in FcR- and CR3-induced activation and for properly functioning signal transduction involved in the generation of oxygen radicals.
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| 30. |
- Fröbert, Ole, 1964-, et al.
(författare)
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Platelet function in brown bear (Ursus arctos) compared to man
- 2010
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Ingår i: Thrombosis Journal. - London, UK : BioMed Central (BMC). - 1477-9560. ; 8, s. 11-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Information on hemostasis and platelet function in brown bear (Ursus arctos) is of importance for understanding the physiological, protective changes during hibernation.Objective: The study objective was to document platelet activity values in brown bears shortly after leaving the den and compare them to platelet function in healthy humans.Methods: Blood was drawn from immobilized wild brown bears 7-10 days after leaving the den in mid April. Blood samples from healthy human adults before and after clopidogrel and acetylsalicylic acid administration served as control. We analyzed blood samples by standard blood testing and platelet aggregation was quantified after stimulation with various agonists using multiple electrode aggregometry within 3 hours of sampling.Results: Blood samples were collected from 6 bears (3 females) between 1 and 16 years old and from 10 healthy humans. Results of adenosine diphosphate, aspirin, and thrombin receptor activating peptide tests in bears were all half or less of those in humans. Platelet and white blood cell counts did not differ between species but brown bears had more and smaller red blood cells compared with humans.Conclusion: Using three different tests, we conclude that platelet function is lower in brown bears compared to humans. Our findings represent the first descriptive study on platelet function in brown bears and may contribute to explain how bears can endure denning without obvious thrombus building. However, the possibility that our findings reflect test-dependent and not true biological variations in platelet reactivity needs further studies.
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| 31. |
- Hedbrant, Alexander, 1987-, et al.
(författare)
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Effects on white blood cell counts and the NLRP3 inflammasome due to dust and cobalt exposure in the hard metal industry
- 2022
-
Ingår i: Biomarkers. - : Taylor & Francis. - 1354-750X .- 1366-5804. ; , s. 60-70
-
Tidskriftsartikel (refereegranskat)abstract
- 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.MATERIAL 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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| 32. |
- Hedbrant, Alexander, Ph.D, 1987-, et al.
(författare)
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Occupational quartz and particle exposure affect systemic levels of inflammatory markers related to inflammasome activation and cardiovascular disease
- 2023
-
Ingår i: Environmental Health. - : BioMed Central (BMC). - 1476-069X. ; 22:1
-
Tidskriftsartikel (refereegranskat)abstract
- 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)-1β, 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-1β 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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| 33. |
- Hedbrant, Alexander, 1987-, et al.
(författare)
-
Quartz Dust Exposure Affects NLRP3 Inflammasome Activation and Plasma Levels of IL-18 and IL-1Ra in Iron Foundry Workers
- 2020
-
Ingår i: Mediators of Inflammation. - : Hindawi Publishing Corporation. - 0962-9351 .- 1466-1861.
-
Tidskriftsartikel (refereegranskat)abstract
- 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-) 1β 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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| 34. |
- Herring, Matthew, et al.
(författare)
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Exposing kinetic disparities between inflammasome readouts using time-resolved analysis
- 2024
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Ingår i: Heliyon. - : Elsevier. - 2405-8440. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- 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-1β 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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| 35. |
- Hussain, Shahida, 1978-, et al.
(författare)
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N-acetylcysteine and azithromycin affect the innate immune response in cystic fibrosis bronchial epithelial cells in vitro
- 2015
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Ingår i: Experimental Lung Research. - London, UK : Informa Healthcare. - 0190-2148 .- 1521-0499. ; 41:5, s. 251-260
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 36. |
- Hylén, Ulrika, 1977-, et al.
(författare)
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Alterations in inflammasome-related immunometabolites in individuals with severe psychiatric disorders
- 2023
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Ingår i: BMC Psychiatry. - : BioMed Central (BMC). - 1471-244X. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- 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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| 37. |
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| 38. |
- Hylén, Ulrika, 1977-
(författare)
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Immunopsychiatry from a transdiagnostic perspective : the immunometabolic interplay
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background/Objective: Psychiatric disorders are common and they significantly impact quality of life. It has been proposed that inflammatory processescontribute to the emergence of psychiatric disorders. In addition to inflammation, disturbances in metabolic pathways have been seen in individuals with various psychiatric disorders. At the interface between inflammation and metabolism stands the Nod-like receptor 3 (NLRP3) inflammasome, which is anintracellular protein complex responsible for cleaving members of the interleukin-1(IL-1) to their active forms. The overall aim of this thesis project was tounderstand the interplay between metabolism and inflammation in a transdiagnostic cohort of individuals with severe psychiatric disorders.Methods: Patients with severe psychiatric disorder (n=39) and age- and sexmatched healthy controls (n=39) were included in the studies. Psychiatric diagnoses, comorbidities, severity, and functioning were measured using a numberof validated assessment scales. Biological parameters, such as circulating immune markers, gene expression, and metabolites were analyzed using electrochemiluminescence immunoassay, qPCR, and UHPLC-MSMS, respectively. Results: The results revealed that in individuals with psychiatric disorders, immune cells were primed in regard to the NLRP3 inflammasome, with elevatedinflammasome-related cytokine levels, regardless of diagnosis. In addition, positive metabolic inflammasome regulators, such as lactic acid, serine, and glutamine were significantly higher in the patients; the main metabolic pathwaysthat were affected included arginine and proline metabolism and tryptophan metabolism. A number of these parameters also correlated with the patients’ disease severity. Lastly, the patients as a group displayed transdiagnosticchanges in immune–lipid pathways. In particular, strong associations could beobserved between two triglycerides and one ether phospholipid, with the inflammatory markers osteopontin and IL-1Ra.Conclusion: Severe psychiatric disorders are associated with changes in the inflammasome system and its corresponding cytokines, as well as with metabolicdysregulation. The data indicate that, while these systems are known to be associated, their interplay seems limited to relatively few inflammatory mediatorsand metabolites in this patient group. Lastly, while large overlaps were seen between different primary diagnoses, unifying, transdiagnostic patterns of inflammatory and metabolic dysregulation were weak; further studies with a largercohort are needed to examine this issue.
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| 39. |
- Hylén, Ulrika, 1977-, et al.
(författare)
-
Increased inflammasome activity in markedly ill psychiatric patients : An explorative study
- 2020
-
Ingår i: Journal of Neuroimmunology. - : Elsevier. - 0165-5728 .- 1872-8421. ; 339
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate inflammatory perturbations in 40 patients with severe and complex psychiatric disorders by studying the activity of the NLRP3 inflammasome, with a trans-diagnostic approach. Gene expression of CASP1, NLRP3, PYCARD, IL1B, IL1RN, TNF showed a significant increase in the patient group compared to a matched control group. Plasma levels of IL1Ra, IL-18, TNF, IL-6 and CRP were increased in the patient group. Within the patient group, increased gene expression of inflammatory markers correlated with increased disease severity. The findings support the inflammation hypothesis for markedly ill psychiatric patients across diagnostic groups.
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| 40. |
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| 41. |
- Hylén, Ulrika, 1977-, et al.
(författare)
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Potential Transdiagnostic Lipid Mediators of Inflammatory Activity in Individuals With Serious Mental Illness
- 2021
-
Ingår i: Frontiers in Psychiatry. - : Frontiers Media S.A.. - 1664-0640. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Mental disorders are heterogeneous and psychiatric comorbidities are common. Previous studies have suggested a link between inflammation and mental disorders. This link can manifest as increased levels of proinflammatory mediators in circulation and as signs of neuroinflammation. Furthermore, there is strong evidence that individuals suffering from psychiatric disorders have increased risk of developing metabolic comorbidities. Our group has previously shown that, in a cohort of low-functioning individuals with serious mental disorders, there is increased expression of genes associated with the NLRP3 inflammasome, a known sensor of metabolic perturbations, as well as increased levels of IL-1-family cytokines. In the current study, we set out to explore the interplay between disease-specific changes in lipid metabolism and known markers of inflammation. To this end, we performed mass spectrometry-based lipidomic analysis of plasma samples from low-functioning individuals with serious mental disorders (n = 39) and matched healthy controls (n = 39). By identifying non-spurious immune-lipid associations, we derived a partial correlation network of inflammatory markers and molecular lipids. We identified levels of lipids as being altered between individuals with serious mental disorders and controls, showing associations between lipids and inflammatory mediators, e.g., osteopontin and IL-1 receptor antagonist. These results indicate that, in low-functioning individuals with serious mental disorders, changes in specific lipids associate with immune mediators that are known to affect neuroinflammatory diseases.
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| 42. |
- Klasson, Maria, 1977-
(författare)
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Cobalt in the hard metal production industry : exposure via inhalation and skin and the inflammatory response in human keratinocytes
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cobalt is a strong sensitizer and can cause contact allergy upon both direct contact or from airborne exposure on the skin. In the skin, keratinocytes are the first cells to come in contact with the metal and will react and respond to the danger by triggering an alarm system resulting in an inflammatory response in the skin. Keratinocytes have been shown to produce IL-1β, which is one of the most potent inflammatory agents in our body and is associated with a variety of diseases.The aims of this thesis was to investigate cobalt air concentrations for different particle fractions for possible use as proxies for other article measures and to examine if cobalt skin and inhalable air exposure contributes to uptake. Also, to investigate the effect of cobalt on cultured human keratinocyte cell viability, pro-inflammatory cytokine/chemokine release and NLRP3 inflammasome activation using cells cultured at low or high calcium (the latter yielding a more differentiated cell type).Air exposure to cobalt was found in all departments and for all work tasks in the hard metal production facility and exposures were in general below the Swedish OEL for inhalable cobalt. The highest exposure levels were found in the powder production department and for laboratory and furnace work. Good correlations for the mass based measures enable us to use the findings for future references. When personal inhalable air levels of cobalt, cobalt skin levels skin and biological monitoring of cobalt in blood were analysed, the skin exposure was determined to be import as a route of uptake. Skin exposure to cobalt in the hard metal industry, could further affect the total uptake in the same order of magnitude as air exposure. In vitro investigations of cobalt using the human keratinocyte cell line HaCaT, showed that CoCl2 triggered an alarm system in cells where the proinflammatory cytokines/chemokines IL-6, CXCL8 and CCL2, known to be involved in skin inflammation, were secreted in a time- and dosedependent manner. Comparing HaCaT cells of high- and low differentiation stages indicated that the effect of cobalt chloride on cell toxicity occurs throughout the living epidermis. CoCl2 exposure also resulted in secretion of the proinflammatory cytokines IL-1β and IL-18, and caspase-1, which indicates activation of the NLRP3 inflammasome in the cells. CoCl2 regulates the inflammasome both as primer and as an activator. Our mRNA results indicates a negative feedback mechanism in the inflamamsome due to the exposure. The inflammatory response in general is more dose than time dependent, which be important for understanding the mechanisms of allergic sensitization.
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| 43. |
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| 44. |
- Klasson, Maria, 1977-, et al.
(författare)
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Dermal exposure to cobalt studied in vitro in keratinocytes : effects of cobalt exposure on inflammasome activated cytokines, and mRNA response
- 2021
-
Ingår i: Biomarkers. - : Taylor & Francis. - 1354-750X .- 1366-5804. ; 26:8, s. 674-684
-
Tidskriftsartikel (refereegranskat)abstract
- 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-1 beta, 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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| 45. |
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| 46. |
- Klasson, Maria, 1977-, et al.
(författare)
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Dose- and time-dependent changes in viability and IL-6, CXCL8 and CCL2 production by HaCaT-cells exposed to cobalt : Effects of high and low calcium growth conditions
- 2021
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sensitization requires exposure to an allergen with subsequent production of a "danger "signal. In the skin, keratinocytes are the main producers of these signals.OBJECTIVE: To compare dose- and time-effects of cobalt on the viability of and cytokine release from HaCaT cells cultured at low or high calcium.METHOD: To model two separate states of differentiation of keratinocytes, HaCaT cells were cultured under low or high calcium conditions. HaCaT were exposed to different concentrations of cobalt chloride (10 μm to 5 mM) over time (30 minutes- 48 hours). Cell viability was measured with the Cell-Titer Blue Viability assay. Cytokine production was measured using a bead-based immunoassay and flow cytometry. Gene expression was quantified using qPCR. Data was analyzed by ANOVA and linear mixed model.RESULTS: Viability of the cells was dose- and time-dependent. A linear mixed statistical model showed that cobalt exposure induces increase in IL-6, CXCL8 and CCL2 production over time and whereas increase of IL-6 and a decrease of CCL2 was associated with increasing cobalt chloride concentrations. When comparing the cells incubated under high and low calcium conditions, the more differentiated cells in the high concentration were found to exert a stronger response in terms of IL-6 release.CONCLUSIONS: Our data suggest that cobalt chloride triggered an alarm system in HaCaT cells, and proinflammatory cytokines/chemokines were secreted in a dose- and time-dependent manner. When high and low calcium incubations were compared, the difference was seen only for IL-6. These findings indicate that the effect of cobalt chloride on cell toxicity occurs throughout the living epidermis.
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| 47. |
- Krantz, Marcus, 1975-, et al.
(författare)
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A detailed molecular network map and model of the NLRP3 inflammasome
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- 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-1β 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-1β 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.
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| 48. |
- Lönn, Johanna, 1982-, et al.
(författare)
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Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition
- 2012
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Ingår i: Results in Immunology. - : Elsevier BV. - 2211-2839. ; 2, s. 7-12
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocyte growth factor (HGF) is an angiogenic, cardioprotective factor important for tissue and vascular repair. High levels of HGF are associated with chronic inflammatory diseases, such as coronary artery disease (CAD) and periodontitis, and are suggested as a marker of the ongoing atherosclerotic event in patients with CAD. Periodontal disease is more prevalent among patients with CAD than among healthy people. Recent studies indicate a reduced biological activity of HGF in different chronic inflammatory conditions. Biologically active HGF has high affinity to heparan sulfate proteoglycan (HSPG) on cell-membrane and extracellular matrix. The aim of the study was to investigate the serum concentration and the biological activity of HGF with ELISA and surface plasmon resonance (SPR), respectively, before and at various time points after percutaneous coronary intervention (PCI) in patients with CAD, and to examine the relationship with periodontal condition. The periodontal status of the CAD patients was examined, and the presence of P. gingivalis in periodontal pockets was analyzed with PCR. The HGF concentration was significantly higher, at all time-points, in patients with CAD compared to the age-matched controls (P< 0.001), but was independent of periodontal status. The HGF concentration and the affinity to HSPG adversely fluctuated over time, and the biological activity increased one month after intervention in patients without periodontitis. We conclude that elevated concentration of HGF but with reduced biological activity might indicate a chronic inflammatory profile in patients with CAD and periodontitis.
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| 49. |
- Midtbö, Kristine, 1991-, et al.
(författare)
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Molecularly Distinct NLRP3 Inducers Mediate Diverse Ratios of Interleukin-1 β and Interleukin-18 from Human Monocytes
- 2020
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Ingår i: Mediators of Inflammation. - : Hindawi Publishing Corporation. - 0962-9351 .- 1466-1861. ; 2020
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Tidskriftsartikel (refereegranskat)abstract
- Inflammasomes cleave and activate interleukin- (IL-) 1β and IL-18 which have both shared and unique biological functions. IL-1β 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-1β has served as the prototypic indicator of inflammasome activation, few studies have compared the potential differences in IL-1β 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-1β 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-1β, 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-1β ratio. The difference in the IL-18 : IL-1β 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-1β and IL-18 into account and moving away from an on/off perspective of inflammasome activation.
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| 50. |
- Månsson, Emeli, 1978-, et al.
(författare)
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Lower activation of caspase-1 by Staphylococcus epidermidis isolated from prosthetic joint infections compared to commensals
- 2018
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Ingår i: Journal of bone and joint infection. - : IVYSPRING. - 2206-3552. ; 3:1, s. 10-14
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Tidskriftsartikel (refereegranskat)abstract
- Nosocomial sequence types of Staphylococcus epidermidis dominate in prosthetic joint infections. We examined caspase-1 activation in human neutrophils after incubation with Staphylococcus epidermidis isolated from prosthetic joint infections and normal skin flora. Active caspase-1 was lower after incubation with isolates from prosthetic joint infections than after incubation with commensal isolates. Both host and isolate dependent differences in active caspase-1 were noted. Our results indicate that there might be a host-dependent incapacity to elicit a strong caspase-1 response towards certain strains of S. epidermidis. Further experiments with a larger number of individuals are warranted.
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