Inflammation is associated with development of atherosclerosis, and cholesterol crystals (CC) have long been recognized as a hallmark of atherosclerotic lesions. CC appear early in the atheroma ...development and trigger inflammation by NLRP3 inflammasome activation. In this study we hypothesized whether CC employ the complement system to activate inflammasome/caspase-1, leading to release of mature IL-1β, and whether complement activation regulates CC-induced cytokine production. In this study we describe that CC activated both the classical and alternative complement pathways, and C1q was found to be crucial for the activation. CC employed C5a in the release of a number of cytokines in whole blood, including IL-1β and TNF. CC induced minimal amounts of cytokines in C5-deficient whole blood, until reconstituted with C5. Furthermore, C5a and TNF in combination acted as a potent primer for CC-induced IL-1β release by increasing IL-1β transcripts. CC-induced complement activation resulted in upregulation of complement receptor 3 (CD11b/CD18), leading to phagocytosis of CC. Also, CC mounted a complement-dependent production of reactive oxygen species and active caspase-1. We conclude that CC employ the complement system to induce cytokines and activate the inflammasome/caspase-1 by regulating several cellular responses in human monocytes. In light of this, complement inhibition might be an interesting therapeutic approach for treatment of atherosclerosis.
We investigated temporal trends of blood serum levels of 13 perfluorinated alkyl acids (PFAAs) and perfluorooctane sulfonamide (FOSA) in primiparous women (N = 413) from Uppsala County, Sweden, ...sampled 3 weeks after delivery 1996–2010. Levels of the short-chain perfluorobutane sulfonate (PFBS) and perfluorohexane sulfonate (PFHxS) increased 11%/y and 8.3%/y, respectively, and levels of the long-chain perfluorononanoate (PFNA) and perfluorodecanoate (PFDA) increased 4.3%/y and 3.8%/y, respectively. Concomitantly, levels of FOSA (22%/y), perfluorooctane sulfonate (PFOS, 8.4%/y), perfluorodecane sulfonate (PFDS, 10%/y), and perfluorooctanoate (PFOA, 3.1%/y) decreased. Thus, one or several sources of exposure to the latter compounds have been reduced or eliminated, whereas exposure to the former compounds has recently increased. We explored if maternal levels of PFOS, PFOA, and PFNA during the early nursing period are representative for the fetal development period, using serial maternal serum samples, including cord blood (N = 19). PFAA levels in maternal serum sampled during pregnancy and the nursing period as well as in cord blood were strongly correlated. Strongest correlations between cord blood levels and maternal levels were observed for maternal serum sampled shortly before or after the delivery (r = 0.70–0.89 for PFOS and PFOA). A similar pattern was observed for PFNA, although the correlations were less strong due to levels close to the method detection limit in cord blood.
► Fish, meat, dairy products, eggs and fat/oils were analyzed for persistent organic pollutants (POPs) followed by per capita intake calculations. ► The highest levels of PCDD/F, PCB, PBDE, HBCD and ...chlorinated pesticides were found in the fish/fish products. ► The levels and intake of different POPs from food of animal origin in the market basket of 2005 seem to have decreased since the market basket study in 1999.
Based on consumption data statistics, food items from four regions in Sweden were sampled in a so-called market basket study. Food items from five food groups, i.e. fish, meat, dairy products, eggs and fat/oils, were analyzed for persistent organic pollutants (POPs) followed by per capita intake calculations. The highest levels of PCDD/F, PCB, PBDE, HBCD and chlorinated pesticides were found in the fish/fish products. The estimated market basket per capita intake of PCDD/F and dl-PCB was 0.7
pg WHO-TEQ
kg
bw
−1
d
−1 (TEFs from 1998). The intake of ∑PCB was estimated to 4.9
ng
kg
bw
−1
d
−1 and fish was found to be the major contributor with 64%. The intake of ∑PBDE was found to be 0.7
ng
kg
bw
−1
d
−1. Fish (38%) and dairy products (31%) were the largest contributors to the total PBDE intake. The intake of HBCD was estimated to 0.14
ng
kg
bw
−1
d
−1. HBCD mainly came from fish (65%), but also dairy products (24%) and meat (10%) contributed. Also regarding the chlorinated pesticides, fish was found to be the major contributor, with 51% of the ∑DDT coming from fish. The intake of ∑DDT, ∑HCH and HCB was 4.0, 1.0 and 1.1
ng
kg
bw
−1
d
−1, respectively. Most of the ∑HCH and HCB originate from dairy products (43% and 55%, respectively). This study shows that the levels, and intake, of different POPs from food of animal origin in the market basket of 2005 seem to have decreased since the market basket study in 1999.
Staphylococcus aureus may cause serious infections and is one of the most lethal and common causes of sepsis. TLR2 has been described as the main pattern recognition receptor that senses S. aureus ...and elicits production of proinflammatory cytokines via MyD88 -: NF-κB signaling. S. aureus can also induce the production of IFN-β, a cytokine that requires IFN regulatory factors (IRFs) for its transcription, but the signaling mechanism for IFN-β induction by S. aureus are unclear. Surprisingly, we demonstrate that activation of TLR2 by lipoproteins does not contribute to IFN-β production but instead can suppress the induction of IFN-β in human primary monocytes and monocyte-derived macrophages. The production of IFN-β was induced by TLR8-mediated sensing of S. aureus RNA, which triggered IRF5 nuclear accumulation, and this could be antagonized by concomitant TLR2 signaling. The TLR8-mediated activation of IRF5 was dependent on TAK1 and IκB kinase (IKK)β, which thus reveals a physiological role of the recently described IRF5-activating function of IKKβ. TLR8 -: IRF5 signaling was necessary for induction of IFN-β and IL-12 by S. aureus, and it also contributed to the induction of TNF. In conclusion, our study demonstrates a physiological role of TLR8 in the sensing of entire S. aureus in human primary phagocytes, including the induction of IFN-β and IL-12 production via a TAK1 -: IKKβ -: IRF5 pathway that can be inhibited by TLR2 signaling.
In the present study our main focus was blood serum levels and time trends of the fully brominated diphenyl ether (PBDE) BDE-209 in Swedish first-time mothers, as relatively a few human data on this ...congener are currently available. Also, levels and temporal trends in serum of other more commonly reported PBDE congeners and HBCD were studied. In an ongoing study on POPs in Uppsala Primiparas (POPUP), serum samples (N=413) from first-time mothers from 1996 to 2010 were used. Pooling of individual samples (5–25 individuals/pool, approx. 3 pools/year) resulted in 36 pooled samples used for PBDE/HBCD analysis on GC-LRMS. In addition, serum/breast milk correlations for PBDE and HBCD levels in 30 paired samples from individual mothers sampled 2010 were studied.
The mean serum level of BDE-209 (1.3ng/g lipid wt.) was highest of all studied PBDE congeners, followed by BDE-47 and BDE-153. There was no significant temporal trend for BDE-209 during the study period, whereas the levels of BDE-47, BDE-99, BDE-100 and of HBCD decreased significantly in pooled serum 1996–2010. After omission of one outlier, a significant increasing trend was observed for BDE-153. The serum/milk PBDE quotients in paired individual samples from 2010 ranged from 0.83 to 17, with the highest quotient for BDE-209. Differences in PBDE transfer from blood to milk are probably related to molecular weight or size. The correlations between serum and milk levels of tetra- to hexa-brominated congeners were generally strong (r=0.83–0.97), but weaker for BDE-183 (r=0.57) and BDE-209 (r=0.38). Regarding HBCD, serum levels in 2010 were mostly beneath LOQ which made serum/milk quotients impossible. The decreasing levels of some BFR compounds in serum over time show that exposures have decreased after the production and use of some of these substances have been restricted. The lack of temporal trend of BDE-209 suggests that the human exposure to this congener in Sweden has been stable for more than a decade.
•Pooled serum samples from Swedish mothers (1996–2010) were analysed for PBDEs.•Highest mean serum level of BDE-209 (1.3ng/g lipid), then BDE-47 and BDE-153.•Time trend decreased for BDE-47, -99, -100; increased for BDE-153; no trend for BDE-209.•Good association between levels in serum and in breast milk (2010 year's samples).•Increased serum/breast milk ratio favours serum analyses of high-brominated BDEs.
In 2012 a contamination of drinking water with perfluoroalkyl acids (PFAAs) was uncovered in the City of Uppsala, Sweden. The aim of the present study was to determine how these substances have been ...distributed from the contamination source through the groundwater to the drinking water and how the drinking water exposure has influenced the levels of PFAAs in humans over time. The results show that PFAA levels in groundwater measured 2012–2014 decreased downstream from the point source, although high ΣPFAA levels (>100ng/L) were still found several kilometers from the point source in the Uppsala aquifer. The usage of aqueous film forming fire-fighting foams (AFFF) at a military airport in the north of the city is probably an important contamination source. Computer simulation of the distribution of PFAA-contaminated drinking water throughout the City using a hydraulic model of the pipeline network suggested that consumers in the western and southern parts of Uppsala have received most of the contaminated drinking water. PFAA levels in blood serum from 297 young women from Uppsala County, Sweden, sampled during 1996–1999 and 2008–2011 were analyzed. Significantly higher concentrations of perfluorobutane sulfonic acid (PFBS) and perfluorohexane sulfonic acid (PFHxS) were found among women who lived in districts modeled to have received contaminated drinking water compared to unaffected districts both in 1996–1999 and 2008–2011, indicating that the contamination was already present in the late 1990s. Isomer-specific analysis of PFHxS in serum showed that women in districts with contaminated drinking water also had an increased percentage of branched isomers. Our results further indicate that exposure via contaminated drinking water was the driving factor behind the earlier reported increasing temporal trends of PFBS and PFHxS in blood serum from young women in Uppsala.
•Urban ground water wells have been contaminated with PFAA.•The usage of fire-fighting foams at a military airport is probably a main source.•Temporal/spatial variability of contaminated drinking water distribution was large.•Women drinking the water had elevated serum concentrations of PFBS and PFHxS.•Elevated br PFHxS isomers are a potential marker for drinking water PFHxS exposure.
4-Nonylphenol (NP) and bisphenol A (BPA) are phenolic substances used in high volumes by the industry. Studies on cells and in experimental animals have shown that both these compounds can be ...classified as estrogenic hormone disrupters. Information about the exposure of humans to NP and BPA is still scarce, especially regarding levels in human blood. The first aim of this study was to investigate possible sources of NP and BPA exposure from food, by analyzing the levels of NP and BPA from a Swedish food market basket, based on the Swedish per capita food consumption. A second aim was to investigate blood serum levels of NP and BPA, as well as NP-ethoxylates, among young women in Sweden (n=100). Moreover, associations between food consumption and blood NP and BPA levels were studied. In food, NP was to some extent found at levels above limit of quantification (LOQ 20ng/g fresh weight) in fruits, cereal products, vegetables, and potatoes. BPA levels above LOQ (2ng/g fresh weight) were found in fish, meats, potatoes, and dairy products. The estimated mean intakes per capita were (medium bound) 27μg NP/day and 3.9μg BPA/day, showing that food is a source of BPA and NP in the general Swedish population. In blood serum, free NP above limit of detection (LOD 0.5ng/g) was detected in 46% of the study participants while detectable levels of total NP (LOD 0.8ng/g) were observed in 43%. The corresponding percentages for BPA were 25% and 22%, respectively. The results indicate that there is a continuous source of exposure to NP and BPA that is high enough for free NP and BPA to be detected in some consumers. Among the participants with quantifiable levels of free and total NP (n=38), 85% (median, range: 38–112%) of the NP was present as free NP. For BPA 76% (49–109%) was detected as free BPA (n=15). All women had levels of ethoxylates of NP below LOD (0.1–0.7ng/g). A significantly higher total consumption of fruits and vegetables was reported in questionnaires by participants with NP levels at or above LOD than among women with levels below LOD. This result is supporting the market basket results of relatively high NP levels in these types of food.
► NP and BPA were found in certain food groups in the Swedish market basket from 2005. ► More than 30% of the sampled women had levels of NP and BPA in blood serum. ► Consumption of fruits and vegetables, and serum NP levels were positively associated.
Cholesterol crystals (CC) are abundant in atherosclerotic plaques and promote inflammatory responses via the complement system and inflammasome activation. Cyclic oligosaccharide ...2-hydroxypropyl-β-cyclodextrin (BCD) is a compound that solubilizes lipophilic substances. Recently we have shown that BCD has an anti-inflammatory effect on CC via suppression of the inflammasome and liver X receptor activation. The putative effects of BCD on CC-induced complement activation remain unknown. In this study, we found that BCD bound to CC and reduced deposition of Igs, pattern recognition molecules, and complement factors on CC in human plasma. Furthermore, BCD decreased complement activation as measured by terminal complement complex and lowered the expression of complement receptors on monocytes in whole blood in response to CC exposure. In line with this, BCD also reduced reactive oxygen species formation caused by CC in whole blood. Furthermore, BCD attenuated the CC-induced proinflammatory cytokine responses (e.g., IL-1α, MIP-1α, TNF, IL-6, and IL-8) as well as regulated a range of CC-induced genes in human PBMC. BCD also regulated complement-related genes in human carotid plaques treated ex vivo. Formation of terminal complement complex on other complement-activating structures such as monosodium urate crystals and zymosan was not affected by BCD. These data demonstrate that BCD inhibits CC-induced inflammatory responses, which may be explained by BCD-mediated attenuation of complement activation. Thus, these findings support the potential for using BCD in treatment of atherosclerosis.
High body burdens of persistent halogenated organic pollutants (POPs) among pregnant and nursing women are of concern because of exposure of the growing foetus and breast-feeding infant. We examined ...the temporal trends of polychlorinated biphenyls (PCBs), dibenzo-
p-dioxin (PCDDs) and dibenzofurans (PCDFs), polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) in milk samples from Swedish women. POPs were analysed in individual mother's milk samples from randomly recruited primiparas (
N=335) who lived in Uppsala County and delivered between 1996 and 2006. Results were adjusted for life-style factors that are associated with POP body burdens. PCB levels declined 3.9–8.6% per year. The levels of PCDDs decreased faster (6–9% per year) than the levels of PCDFs (3–6% per year). Temporal trends of PBDEs did not follow any consistent pattern. Concentrations of BDE-47 and BDE-99 decreased, while the concentrations of BDE-153 increased. No change in BDE-100 concentrations was observed. In most samples, concentrations of HBCD were below the quantification limit (<0.20
ng/g lipid). Generally, adjustment of the temporal trends of PCBs and PCDD/Fs for personal characteristics of the mothers (age, body mass index (BMI), weight changes during and after pregnancy) resulted in faster declining rates, with age having the greatest influence. The age of the participating mothers increased during the study period, and since the POP levels increased with increasing age, this counteracted the decreasing temporal trends in the unadjusted model. It is consequently important to include personal characteristics in the analysis of temporal trends of POPs. Compound-specific temporal trends are probably caused by differences in sources of exposure, as well as by differences in persistence between compounds.
Chronic inflammation of the arterial wall is a key element in the development of atherosclerosis, and cholesterol crystals (CC) that accumulate in plaques are associated with initiation and ...progression of the disease. We recently revealed a link between the complement system and CC-induced inflammasome caspase-1 activation, showing that the complement system is a key trigger in CC-induced inflammation. HDL exhibits cardioprotective and anti-inflammatory properties thought to explain its inverse correlation to cardiovascular risk. In this study, we sought to determine the effect of reconstituted HDL (rHDL) on CC-induced inflammation in a human whole blood model. rHDL bound to CC and inhibited the CC-induced complement activation as measured by soluble terminal C5b-9 formation and C3c deposition on the CC surface. rHDL attenuated the amount of CC-induced complement receptor 3 (CD11b/CD18) expression on monocytes and granulocytes, as well as reactive oxygen species generation. Moreover, addition of CC to whole blood resulted in release of proinflammatory cytokines that were inhibited by rHDL. Our results support and extend the notion that CC are potent triggers of inflammation, and that rHDL may have a beneficial role in controlling the CC-induced inflammatory responses by inhibiting complement deposition on the crystals.
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