| 51. |
- Lönn, Johanna, 1982-, et al.
(author)
-
Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition
- 2012
-
In: Results in Immunology. - : Elsevier BV. - 2211-2839. ; 2, s. 7-12
-
Journal article (peer-reviewed)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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| 52. |
- Midtbö, Kristine, 1991-, et al.
(author)
-
Molecularly Distinct NLRP3 Inducers Mediate Diverse Ratios of Interleukin-1 β and Interleukin-18 from Human Monocytes
- 2020
-
In: Mediators of Inflammation. - : Hindawi Publishing Corporation. - 0962-9351 .- 1466-1861. ; 2020
-
Journal article (peer-reviewed)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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| 53. |
- Månsson, Emeli, 1978-, et al.
(author)
-
Lower activation of caspase-1 by Staphylococcus epidermidis isolated from prosthetic joint infections compared to commensals
- 2018
-
In: Journal of bone and joint infection. - : IVYSPRING. - 2206-3552. ; 3:1, s. 10-14
-
Journal article (peer-reviewed)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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| 54. |
- Månsson, Emeli, 1978-
(author)
-
Molecular epidemiology of Staphylococcus epidermidis in prosthetic joint infections
- 2019
-
Doctoral thesis (other academic/artistic)abstract
- Staphylococcus epidermidis is ubiquitous in the human microbiota, but also an important pathogen in healthcare-associated infections, such as prosthetic joint infections (PJIs). In this thesis, aspects of the molecular epidemiology of S. epidermidis in PJIs were investigated with the aim of improving our understanding of the pre- and perioperative measures required to reduce the incidence of S. epidermidis PJIs.In Paper I, S. epidermidis retrieved from air sampling in the operating field during arthroplasty was characterized by multilocus sequence typing and antibiotic susceptibility testing. No isolates belonging to sequence types (STs) 2 and 215, previously associated with PJIs, were found in the air of the operating field. During air sampling, several Staphylococcus pettenkoferi isolates were identified, and as a spin-off of Paper I, the genomic relatedness of these isolates to S. pettenkoferi isolates from blood cultures was described in Paper II.In Paper III, genetic traits distinguishing S. epidermidis isolated from PJIs were determined using genome-wide association study accounting for population effects after whole-genome sequencing (WGS) of a population- based 10-year collection of S. epidermidis isolates from PJIs and of nasal isolates retrieved from patients scheduled for arthroplasty. Genes associated with antimicrobial agents used for prophylaxis in arthroplasty, i.e., beta-lactam antibiotics, aminoglycosides, and chlorhexidine, were associated with PJI origin. S. epidermidis from PJIs were dominated by the ST2a, ST2b, ST5, and ST215 lineages.In Paper IV, selective agar plates were used to investigate colonization with methicillin resistant S. epidermidis (MRSE) in patients scheduled for arthroplasty. MRSE were further characterized by WGS. A subset of patients was found to harbour PJI-associated S. epidermidis lineages in their microbiota before hospitalization, but no isolates belonging to the ST2a lineage nor any rifampicin-resistant isolates were retrieved.
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| 55. |
- Månsson, Emeli, 1978-, et al.
(author)
-
Staphylococcus epidermidis from prosthetic joint infections induces lower IL-1 release from human neutrophils than isolates from normal flora
- 2018
-
In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley-Blackwell Publishing Inc.. - 0903-4641 .- 1600-0463. ; 126:8, s. 678-684
-
Journal article (peer-reviewed)abstract
- The aim of this study was to test the hypothesis that Staphylococcus epidermidis isolated from prosthetic joint infections (PJIs) differs from S.epidermidis isolated from normal flora in terms of its capacity to induce activation of caspase-1 and release of IL-1 in human neutrophils. The amount of active caspase-1 was determined over 6h by detecting Ac-YVAD-AMC fluorescence in human neutrophils incubated with S.epidermidis isolates from PJIs (ST2) or normal flora. The amount of IL-1 was detected by ELISA in neutrophil supernatants after 6h of incubation. Mean IL-1 release was lower after incubation with S.epidermidis from PJIs compared to isolates from normal flora, but no statistically significant difference was found in active caspase-1. Substantial inter-individual differences in both active caspase-1 and IL-1 were noted. These results suggest that evasion of innate immune response, measured as reduced capacity to induce release of IL-1 from human neutrophils, might be involved in the predominance of ST2 in S.epidermidis PJIs, but that other microbe-related factors are probably also important.
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| 56. |
- Nikaein, Niloofar, 1989-, et al.
(author)
-
Mathematical models disentangle the role of IL-10 feedbacks in human monocytes upon proinflammatory activation
- 2023
-
In: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 299:10
-
Journal article (peer-reviewed)abstract
- Inflammation is one of the vital mechanisms through which the immune system responds to harmful stimuli. During inflammation, pro and anti-inflammatory cytokines interplay to orchestrate fine-tuned, dynamic immune responses. The cytokine interplay governs switches in the inflammatory response and dictates the propagation and development of the inflammatory response. Molecular pathways underlying the interplay are complex, and time-resolved monitoring of mediators and cytokines is necessary as a basis to study them in detail. Our understanding can be advanced by mathematical models which enable to analyze the system of interactions and their dynamical interplay in detail. We, therefore, used a mathematical modeling approach to study the interplay between prominent pro and anti-inflammatory cytokines with a focus on tumor necrosis factor (TNF) and interleukin 10 (IL-10) in lipopolysaccharide (LPS)-primed primary human monocytes. Relevant time-resolved data were generated by experimentally adding or blocking IL-10 at different time points. The model was successfully trained and could predict independent validation data and was further used to perform simulations to disentangle the role of IL-10 feedbacks during an acute inflammatory event. We used the insight to obtain a reduced predictive model including only the necessary IL-10-mediated feedbacks. Finally, the validated reduced model was used to predict early IL-10 - TNF switches in the inflammatory response. Overall, we gained detailed insights into fine-tuning of inflammatory responses in human monocytes and present a model for further use in studying the complex and dynamic process of cytokine-regulated acute inflammation.
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| 57. |
- Paramel, Geena, 1985-, et al.
(author)
-
CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
- 2013
-
In: Clinical Science. - London, United Kingdom : Portland Press. - 0143-5221 .- 1470-8736. ; 125:8, s. 401-407
-
Journal article (peer-reviewed)abstract
- Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1 beta in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-kappa B (nuclear factor kappa B). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1 beta, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P < 0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.
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| 58. |
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| 59. |
- Rasmussen, Gunlög, et al.
(author)
-
Caspase-1 Inflammasome Activity in Patients with Staphylococcus aureus Bacteremia
- 2019
-
In: Microbiology and immunology. - : Wiley-Blackwell Publishing Inc.. - 0385-5600 .- 1348-0421. ; 63:12, s. 487-499
-
Journal article (peer-reviewed)abstract
- The inflammasome is a multiprotein complex that mediates caspase-1 activation with subsequent maturation of the pro-inflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome is known to be activated by Staphylococcus aureus, one of the leading causes of bacteremia worldwide. Inflammasome activation and regulation in response to bacterial infection have been found to be of importance for a balanced host immune response. However, inflammasome signaling in vivo in humans initiated by S. aureus is currently sparsely studied. The present study therefore aimed to investigate NLRP3 inflammasome activity in 20 S. aureus bacteremia patients, by repeated measurement during the first week of bacteremia, compared with controls. Caspase-1 activity was measured in monocytes and neutrophils by flow cytometry detecting FLICA (Fluorescent Labelled Inhibitor of Caspase-1), while IL-1β and IL-18 was measured by Luminex and ELISA, respectively. As a measure of inflammasome priming, mRNA expression of NLRP3, CASP1 (pro-caspase-1) and IL1B (pro-IL-1β) was analyzed by qPCR. We found induced caspase-1 activity in innate immune cells with subsequent release of IL-18 in patients during the acute phase of bacteremia, indicating activation of the inflammasome. There was substantial inter-individual variation in caspase-1 activity between S. aureus bacteremia patients. We also found an altered inflammasome priming with low mRNA levels of NLRP3 accompanied by elevated mRNA levels of IL1B. This increased knowledge of the individual host immune response in S. aureus bacteremia could provide support in the effort to optimize management and treatment of each individual patient.
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| 60. |
- Sahdo, Berolla, 1984-, et al.
(author)
-
Body temperature during hibernation is highly correlated with a decrease in circulating innate immune cells in the brown bear (Ursus arctos) : a common feature among hibernators?
- 2013
-
In: International Journal of Medical Sciences. - Sydney, Australia : Ivyspring International Publisher. - 1449-1907. ; 10:5, s. 508-514
-
Journal article (peer-reviewed)abstract
- Background: Hibernation involves periods of severely depressed metabolism (torpor) and decreases in body temperature (Tb). Small arctic mammals (<5kg), in which Tb generally drop drastically, display leukopenia during hibernation. This raised the question of whether the decreased leukocyte counts in mammalian hibernators is due to torpor per se or is secondary to low Tb. The present study examined immune cell counts in brown bears (Ursus arctos), where torpor is only associated with shallow decreases in Tb. The results were compared across hibernator species for which immune and Tb data were available.Methods and Results: The white blood cell counts were determined by flow cytometry in 13 bears captured in the field both during summer and winter over 2 years time. Tb dropped from 39.6+/-0.8 to 33.5+/-1.1 degrees C during hibernation. Blood neutrophils and monocytes were lower during hibernation than during the active period (47%, p=0.001; 43%, p=0.039, respectively), whereas no change in lymphocyte counts was detected (p=0.599). Further, combining our data and those from 10 studies on 9 hibernating species suggested that the decline in Tb explained the decrease in innate immune cells (R-2=0.83, p<0.0001).Conclusions: Bears have fewer innate immune cells in circulation during hibernation, which may represent a suppressed innate immune system. Across species comparison suggests that, both in small and large hibernators, Tb is the main driver of immune function regulation during winter dormancy. The lack of a difference in lymphocyte counts in this context requires further investigations.
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| 61. |
- Sahdo, Berolla, 1984-, et al.
(author)
-
Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the nlrp3 inflammasome
-
Other publication (other academic/artistic)abstract
- Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Increased production of IL-1β is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1β, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched noncarrier controls.Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1β and IL-33 were elevated among carriers of combined Q705K/C10X polymorphisms compared to controls, whereas no difference was found for IL- 18 and the other cytokines measured. These data suggest that these combined polymorphisms creates inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.
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| 62. |
- Sahdo, Berolla, 1984-, et al.
(author)
-
Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
- 2013
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
-
Journal article (peer-reviewed)abstract
- Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Increased production of IL-1 beta is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1 beta, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls.Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1 beta and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1 beta as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.
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| 63. |
- Sahdo, Berolla, 1984-, et al.
(author)
-
Propionibacterium acnes activates caspase-1 in human neutrophils
- 2013
-
In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - Hoboken, USA : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 121:7, s. 652-63
-
Journal article (peer-reviewed)abstract
- Propionibacterium acnes is a Gram-positive, slow-growing, anaerobic bacillus, predominantly found as a commensal on the skin and mucous membranes of adults. It is, however, also considered an opportunistic pathogen; mostly associated with acne vulgaris, but rarely also with severe infections such as infective endocarditis, prosthetic joint infections, and deep sternal wound infections following cardiothoracic surgery. In addition, P. acnes has recently been found in high frequency in prostate tissue from patients with prostatitis and prostate cancer. The NOD-like receptors (NLR) act as intracellular sensors of microbial components, and a number of various bacteria have been found to induce assembling and activation of NLR-inflammasomes; leading to a pro-inflammatory response. The inflammasome-mediated formation of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 involves the auto-proteolytic maturation of caspase-1. This study investigated if P. acnes activates inflammasomes. Propionibacterium acnes isolates (n = 29) with diverse origin were used as stimuli for peripheral leukocytes obtained from blood donors (BDs). The activity of inflammasomes was determined by measuring caspase-1 by flow cytometry and cytokine production by ELISA. A significant amount of caspase-1 was found in neutrophils upon P. acnes stimulation, whereas only a modest activation was seen in monocytes. The activation was mainly produced by components of the bacterial cell and no exo-products, because heat-killed and live bacteria caused high activation of caspase-1 as well as cytokine production, whereas the bacterial supernatant elicited minor effect. The response among different BDs varied significantly, almost fivefold. In addition, P. acnes of various origins showed considerable variation, however, the commensal isolates showed a stronger response compared with the invasive. In conclusion, although regarded as a harmless commensal of the skin, P. acnes strongly activates the inflammasome of human peripheral neutrophils.
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| 64. |
- Serhan, Charles N., et al.
(author)
-
The Atlas of Inflammation Resolution (AIR)
- 2020
-
In: Molecular Aspects of Medicine. - : Elsevier. - 0098-2997 .- 1872-9452. ; 74
-
Journal article (peer-reviewed)abstract
- Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de.
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| 65. |
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| 66. |
- Säll, Olof, 1980-, et al.
(author)
-
Prevalence and persistence of Neisseria meningitidis carriage in Swedish university students
- 2023
-
In: Epidemiology and Infection. - : Cambridge University Press. - 0950-2688 .- 1469-4409. ; 151
-
Journal article (peer-reviewed)abstract
- The bacterium Neisseria meningitidis causes life-threatening disease worldwide, typically with a clinical presentation of sepsis or meningitis, but can be carried asymptomatically as part of the normal human oropharyngeal microbiota. The aim of this study was to examine N. meningitidis carriage with regard to prevalence, risk factors for carriage, distribution of meningococcal lineages and persistence of meningococcal carriage. Throat samples and data from a self-reported questionnaire were obtained from 2744 university students (median age: 23 years) at a university in Sweden on four occasions during a 12-month period. Meningococcal isolates were characterised using whole-genome sequencing. The carriage rate among the students was 9.1% (319/3488; 95% CI 8.2-10.1). Factors associated with higher carriage rate were age ≤22 years, previous tonsillectomy, cigarette smoking, drinking alcohol and attending parties, pubs and clubs. Female gender and sharing a household with children aged 0-9 years were associated with lower carriage. The most frequent genogroups were capsule null locus (cnl), group B and group Y and the most commonly identified clonal complexes (cc) were cc198 and cc23. Persistent carriage with the same meningococcal strain for 12 months was observed in two students. Follow-up times exceeding 12 months are recommended for future studies investigating long-term carriage of N. meningitidis.
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| 67. |
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| 68. |
- Tuerxun, Kaya, 1981-, et al.
(author)
-
Cytokine responses to LPS in reprogrammed monocytes are associated with the transcription factor PU.1
- 2022
-
In: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 112:4, s. 679-692
-
Journal article (peer-reviewed)abstract
- Myeloid-derived suppressor cells (MDSCs) are functionally immunosuppressive cells that arise and expand during extensive inflammatory conditions by increased hematopoietic output or reprogramming of immune cells. In sepsis, an increase of circulating MDSCs is associated with adverse outcomes, but unique traits that can be used to identify increased activity of MDSCs are lacking. By using endotoxin tolerance as a model of sepsis-induced monocytic MDSCs (M-MDSC-like cells), this study aims to identify the mediator and transcriptional regulator profile associated with MMDSC activity. After analyzing 180 inflammation-associated proteins, a profile of differentially expressed cytokines was found in M-MDSC-like cells versus normal monocytes stimulated with LPS. These cytokines were associated with 5 candidate transcription factors, where particularly PU.1 showed differential expression on both transcriptional and protein levels in M-MDSC-like cells. Furthermore, inhibition of PU.1 led to increased production of CXCL5 and CCL8 in M-MDSC-like cells indicating its role in regulating the ability of M-M DSC-like cells to recruit other immune cells. Taken together, the study identifies a unique profile in the pattern of immune mediators defining M-MDSC activity upon LPS stimulation, which offers a functional link to their contribution to immunosuppression.
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| 69. |
- Tuerxun, Kaya, 1981-, et al.
(author)
-
Predicting sepsis using a combination of clinical information and molecular immune markers sampled in the ambulance
- 2023
-
In: Scientific Reports. - : Nature Portfolio. - 2045-2322. ; 13:1
-
Journal article (peer-reviewed)abstract
- Sepsis is a time dependent condition. Screening tools based on clinical parameters have been shown to increase the identification of sepsis. The aim of current study was to evaluate the additional predictive value of immunological molecular markers to our previously developed prehospital screening tools. This is a prospective cohort study of 551 adult patients with suspected infection in the ambulance setting of Stockholm, Sweden between 2017 and 2018. Initially, 74 molecules and 15 genes related to inflammation were evaluated in a screening cohort of 46 patients with outcome sepsis and 50 patients with outcome infection no sepsis. Next, 12 selected molecules, as potentially synergistic predictors, were evaluated in combination with our previously developed screening tools based on clinical parameters in a prediction cohort (n = 455). Seven different algorithms with nested cross-validation were used in the machine learning of the prediction models. Model performances were compared using posterior distributions of average area under the receiver operating characteristic (ROC) curve (AUC) and difference in AUCs. Model variable importance was assessed by permutation of variable values, scoring loss of classification as metric and with model-specific weights when applicable. When comparing the screening tools with and without added molecular variables, and their interactions, the molecules per se did not increase the predictive values. Prediction models based on the molecular variables alone showed a performance in terms of AUCs between 0.65 and 0.70. Among the molecular variables, IL-1Ra, IL-17A, CCL19, CX3CL1 and TNF were significantly higher in septic patients compared to the infection non-sepsis group. Combing immunological molecular markers with clinical parameters did not increase the predictive values of the screening tools, most likely due to the high multicollinearity of temperature and some of the markers. A group of sepsis patients was consistently miss-classified in our prediction models, due to milder symptoms as well as lower expression levels of the investigated immune mediators. This indicates a need of stratifying septic patients with a priori knowledge of certain clinical and molecular parameters in order to improve prediction for early sepsis diagnosis.Trial registration: NCT03249597. Registered 15 August 2017.
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| 70. |
- Vallabani, N. V. Srikanth, et al.
(author)
-
Toxicity evaluation of particles formed during 3D-printing : Cytotoxic, genotoxic, and inflammatory response in lung and macrophage models
- 2022
-
In: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 467
-
Journal article (peer-reviewed)abstract
- Additive manufacturing (AM) or "3D-printing" is a ground-breaking technology that enables the production of complex 3D parts. Its rapid growth calls for immediate toxicological investigations of possible human exposures in order to estimate occupational health risks. Several laser-based powder bed fusion AM techniques are available of which many use metal powder in the micrometer range as feedstock. Large energy input from the laser on metal powders generates several by-products, like spatter and condensate particles. Due to often altered physicochemical properties and composition, spatter and condensate particles can result in different toxicological responses compared to the original powder particles. The toxicity of such particles has, however, not yet been investigated. The aim of the present study was to investigate the toxicity of condensate/spatter particles formed and collected upon selective laser melting (SLM) printing of metal alloy powders, including a nickel-chromiumbased superalloy (IN939), a nickel-based alloy (Hastelloy X, HX), a high-strength maraging steel (18Ni300), a stainless steel (316L), and a titanium alloy (Ti6Al4V). Toxicological endpoints investigated included cytotoxicity, generation of reactive oxygen species (ROS), genotoxicity (comet and micronucleus formation), and inflammatory response (cytokine/chemokine profiling) following exposure of human bronchial epithelial cells (HBEC) or monocytes/macrophages (THP-1). The results showed no or minor cytotoxicity in the doses tested (10 100 mu g/mL). Furthermore, no ROS generation or formation of micronucleus was observed in the HBEC cells. However, an increase in DNA strand breaks (detected by comet assay) was noted in cells exposed to HX, IN939, and Ti6Al4V, whereas no evident release of pro-inflammatory cytokine was observed from macrophages. Particle and surface characterization showed agglomeration in solution and different surface oxide compositions compared to the nominal bulk content. The extent of released nickel was small and related to the nickel content of the surface oxides, which was largely different from the bulk content. This may explain the limited toxicity found despite the high Ni bulk content of several powders. Taken together, this study suggests relatively low acute toxicity of condensates/spatter particles formed during SLM-printing using IN939, HX, 18Ni300, 316L, and Ti6Al4V as original metal powders.
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| 71. |
- Verma, Deepti, et al.
(author)
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Gene polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation : relation to common inflammatory diseases?
- 2008
-
In: Arthritis and Rheumatism. - New York, NY : John Wiley & Sons. - 0004-3591 .- 1529-0131. ; 58:3, s. 888-894
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Journal article (peer-reviewed)abstract
- OBJECTIVE: NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1beta (IL-1beta) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome. METHODS: Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1beta production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects. RESULTS: Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL-1beta measured in samples from the patient returned to normal levels after treatment with anakinra. CONCLUSION: Our results indicate that the patient's symptoms were due to elevated levels of IL-1beta, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1beta levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.
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- Verma, Deepti, et al.
(author)
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The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and IL-18 production
- 2012
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In: PLOS ONE. - San Fransisco, USA : Public Library of Science. - 1932-6203. ; 7:4
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Journal article (peer-reviewed)abstract
- Background: The Q705K polymorphism in NLRP3 has been implicated in several chronic inflammatory diseases. In this study, we determine the functional role of this commonly occurring polymorphism using an in-vitro system.Methods / Principle findings: NLRP3-WT and NLRP3-Q705K were retrovirally transduced into the human monocytic cell line THP-1, followed by the assessment of IL-1β and IL-18 levels in the cell culture supernatant. THP-1 cells expressing the above NLRP3 variants were sorted based upon Green Fluorescent Protein (GFP) expression. Cytokine response to alum (one of the most widely used adjuvants in vaccines) in the cells stably expressing NLRP3-WT and NLRP3-Q705K were determined. IL-1β and IL-18 levels were found to be elevated in THP-1 cells transduced with NLRP3-Q705K compared to the NLRP3-WT. Upon exposure to alum, THP-1 cells stably expressing NLRP3-Q705K displayed an increased production of IL-1β, IL-18 and TNF-α, in a caspase-1 and IL-1 receptor-dependent manner.Conclusions: Collectively, these findings show that the Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to an overactive NLRP3 inflammasome. The option of IL-1β blockade may be considered in patients with chronic inflammatory disorders that are unresponsive to conventional treatments.
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