The Paradigm Change of IL-33 in Vascular Biology Demyanets, Svitlana; Stojkovic, Stefan; Huber, Kurt ...
International journal of molecular sciences,
12/2021, Letnik:
22, Številka:
24
Journal Article
Recenzirano
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In this review, we focus on the actual understanding of the role of IL-33 in vascular biology in the context of the historical development since the description of IL-33 as a member of IL-1 ...superfamily and the ligand for ST2 receptor in 2005. We summarize recent data on the biology, structure and signaling of this dual-function factor with both nuclear and extracellular cytokine properties. We describe cellular sources of IL-33, particularly within vascular wall, changes in its expression in different cardio-vascular conditions and mechanisms of IL-33 release. Additionally, we summarize the regulators of IL-33 expression as well as the effects of IL-33 itself in cells of the vasculature and in monocytes/macrophages in vitro combined with the consequences of IL-33 modulation in models of vascular diseases in vivo. Described in murine atherosclerosis models as well as in macrophages as an atheroprotective cytokine, extracellular IL-33 induces proinflammatory, prothrombotic and proangiogenic activation of human endothelial cells, which are processes known to be involved in the development and progression of atherosclerosis. We, therefore, discuss that IL-33 can possess both protective and harmful effects in experimental models of vascular pathologies depending on experimental conditions, type and dose of administration or method of modulation.
Abstract
Microribonucleic acids (miRs) are small, noncoding ribonucleic acids (RNAs), which play an important role in the regulation of platelet function and activity. Several studies proposed a ...mechanistic role of platelet-related miRs in the pathophysiology of coronary artery disease (CAD) and atherothrombosis. Circulating, platelet-related miRs have been proposed as diagnostic, prognostic, as well as treatment response biomarkers in CAD and acute coronary syndrome (ACS). In this review, we summarize recent studies on the role of platelet-related miRs in the regulation of platelet function and activity. Furthermore, we review the studies investigating the role of platelet-related miRs as biomarkers in patients with CAD and ACS.
Background: Careful device programming is necessary to reduce inappropriate antitachycardia pacing (ATP) and shock therapy in recipients of implantable cardioverter-defibrillators (ICD). This ...retrospective study investigated the safety and efficacy of a therapy-reducing programming strategy in comparison with conventional strategies in consecutive ICD recipients of a university cardiac center. Methods and Results: All 1,471 ICD recipients from 2000 to 2015 were analyzed. Individual ICD programming (IND) was used from 2000 to 2005 followed by standard-three-zone programming (STD) until 2010. From 2010 to 2015 therapy-reducing long detection time programming (RED) was established. The mean follow-up was 2.4±1.6, 2.3±1.6 and 1.7±1.2 years in the IND, STD and RED groups, respectively. Switchover from IND to STD revealed a significant reduction in inappropriate ATP (P=0.024) and shock therapy (P<0.001). Further reduction of 58% (RR=0.42, 95% confidence interval CI: 0.17–1.04; P=0.061) in inappropriate ATP and 29% (RR=0.71, 95% CI: 0.29–1.72; P=0.452) in inappropriate shock therapy was achieved by switchover from STD to RED. Kaplan-Meier analysis revealed a significant difference in time until first inappropriate ATP and shock therapy among the 3 groups, being lowest in the RED group (P≤0.001). There was no difference in overall mortality (P=0.416). Conclusions: Defensive ICD programming with prolonged detection times is safe and significantly reduced inappropriate ICD therapies.
Interleukin (IL-33) and the ST2 receptor are implicated in the pathogenesis of atherosclerosis. Soluble ST2 (sST2), which negatively regulates IL-33 signaling, is an established biomarker in coronary ...artery disease and heart failure. Here we aimed to investigate the association of sST2 with carotid atherosclerotic plaque morphology, symptom presentation, and the prognostic value of sST2 in patients undergoing carotid endarterectomy. A total of 170 consecutive patients with high-grade asymptomatic or symptomatic carotid artery stenosis undergoing carotid endarterectomy were included in the study. The patients were followed up for 10 years, and the primary endpoint was defined as a composite of adverse cardiovascular events and cardiovascular mortality, with all-cause mortality as the secondary endpoint. The baseline sST2 showed no association with carotid plaque morphology assessed using carotid duplex ultrasound (B 0.051, 95% CI -0.145-0.248,
= 0.609), nor with modified histological AHA classification based on morphological description following surgery (B -0.032, 95% CI -0.194-0.130,
= 0.698). Furthermore, sST2 was not associated with baseline clinical symptoms (B -0.105, 95% CI -0.432-0.214,
= 0.517). On the other hand, sST2 was an independent predictor for long-term adverse cardiovascular events after adjustment for age, sex, and coronary artery disease (HR 1.4, 95% CI 1.0-2.4,
= 0.048), but not for all-cause mortality (HR 1.2, 95% CI 0.8-1.7,
= 0.301). Patients with high baseline sST2 levels had a significantly higher adverse cardiovascular event rate as compared to patients with lower sST2 (log-rank
< 0.001). Although IL-33 and ST2 play a role in the pathogenesis of atherosclerosis, sST2 is not associated with carotid plaque morphology. However, sST2 is an excellent prognostic marker for long-term adverse cardiovascular outcomes in patients with high-grade carotid artery stenosis.
Foreign body ingestion is a frequently encountered emergency in healthcare institutions. It mostly affects pediatric populations, although it can also affect adults with developmental delays, those ...with psychiatric diseases, drug abusers, and prisoners. Endoscopy is a diagnostic and treatment method for suspected foreign body ingestion. In this article, we discuss a 45-year-old tailor who swallowed a sewing pin while at work. The abdominal X-ray showed a needle-shaped metal shadow in the stomach region. During an upper endoscopy, it was discovered that a sewing pin with a sharp edge was stuck in the pylorus. The sewing pin was extracted endoscopically, and the patient was discharged the same day in good condition. Since the estimated risk of complications of foreign body ingestion in the adult population is about 35%, and the most common complications include impaction, laceration, bleeding, or perforation of the gastrointestinal wall, endoscopic or surgical removal is necessary. This also emphasizes the importance of a careful endoscopic evaluation of some at-risk occupations for foreign body ingestion with or without gastrointestinal complaints.
The maximal aortic diameter is the only clinically applied predictor of abdominal aortic aneurysm (AAA) progression and indicator for surgical repair. Circulating biomarkers resulting from AAA ...pathogenesis are attractive candidates for the diagnosis and prognosis of aneurysmal disease. Due to the reported role of interleukin 33 in AAA development, we investigated the corresponding circulating receptor molecules of soluble suppression of tumorigenesis 2 (sST2) in AAA patients regarding their marker potential in diagnosis and prognosis. We conducted a single-center retrospective cohort study in a diagnostic setting, measuring the circulating serum sST2 protein levels of 47 AAA patients under surveillance, matched with 25 peripheral artery disease (PAD) patients and 25 healthy controls. In a prognostic setting, we analyzed the longitudinal monitoring data of 50 monitored AAA patients. Slow versus fast AAA progression was defined as a <2 or ≥2 mm increase in AAA diameter over 6 months and a <4 or ≥4 mm increase over 12 months. Additionally, the association of circulating serum sST2 and AAA growth was investigated using a specifically tailored log-linear mixed model. Serum sST2 concentrations were significantly increased in AAA patients compared with healthy individuals: the median of AAA patient cohort was 112.72 ng/mL (p = 0.025) and that of AAA patient cohort 2 was 14.32 ng/mL (p = 0.039) versus healthy controls (8.82 ng/mL). Likewise, PAD patients showed significantly elevated sST2 protein levels compared with healthy controls (the median was 12.10 ng/mL; p = 0.048) but similar concentrations to AAA patients. Additionally, sST2 protein levels were found to be unsuited to identifying fast AAA progression over short-term periods of 6 or 12 months, which was confirmed by a log-linear mixed model. In conclusion, the significantly elevated protein levels of sST2 detected in patients with vascular disease may be useful in the early diagnosis of AAA but cannot distinguish between AAA and PAD or predict AAA progression.
Tissue factor (TF) is the primary trigger of coagulation. Elevated levels of TF are found in atherosclerotic plaques, and TF leads to thrombus formation when released upon plaque rupture. Interleukin ...(IL)-33 was previously shown to induce angiogenesis and inflammatory activation of endothelial cells (ECs). Here, we investigated the impact of IL-33 on TF in human ECs, as a possible new link between inflammation and coagulation. IL-33 induced TF mRNA and protein in human umbilical vein ECs and coronary artery ECs. IL-33-induced TF expression was ST2- and NF-κB-dependent, but IL-1-independent. IL-33 also increased cell surface TF activity in ECs and TF activity in ECs-derived microparticles. IL-33-treated ECs reduced coagulation time of whole blood and plasma but not of factor VII-deficient plasma. In human carotid atherosclerotic plaques (n = 57), TF mRNA positively correlated with IL-33 mRNA expression (r = 0.691, p < 0.001). In this tissue, IL-33 and TF protein was detected in ECs and smooth muscle cells by immunofluorescence. Furthermore, IL-33 and TF protein co-localized at the site of clot formation within microvessels in plaques of patients with symptomatic carotid stenosis. Through induction of TF in ECs, IL-33 could enhance their thrombotic capacity and thereby might impact on thrombus formation in the setting of atherosclerosis.
Although previous studies indicated that chronic alcohol abuse (CAA) and alcoholic liver cirrhosis (ALC) are associated with increased bone fragility, understanding bone fragility determinants is ...still modest in these individuals. We used a comprehensive individualized clinical fracture risk assessment approach (vertebral osteodensitometry, femoral osteodensitometry and geometry, and serum bone turnover biomarkers) to compare adult male patients with ALC who have not previously had femoral or vertebral fractures (
= 39), patients with CAA (without liver cirrhosis,
= 78) who have not previously had femoral or vertebral fractures and healthy age- and sex-matched controls (
= 43). Our data suggested that intertrochanteric bone mineral density was significantly lower in ALC and CAA patients than in controls. Also, the trabecular bone score was considerably lower in ALC patients compared with CAA and control individuals. The most significant inter-group differences in femoral geometry were noted on the femoral shaft. Patients with ALC and CAA have a higher 10-year risk of major osteoporotic fractures compared to the controls. Analysis of bone turnover biomarkers showed increased osteoprotegerin and beta-C-terminal telopeptide serum concentrations and decreased insulin growth factor-1 concentrations in patients with ALC compared to CAA and control groups. Our data revealed that bone alterations are present in patients with ALC and CAA even if they did not sustain a nontraumatic bone fracture, but it is also indicative that current bone-assessing clinical methods are not entirely reliable. Thus, future studies should focus on developing a reliable integrative clinical tool that can be used to accurately predict and prevent bone fracture occurrences in patients with ALC and CAA.
Macrophages are versatile cells that can be polarized by the tissue environment to fulfill required needs. Proinflammatory polarization is associated with increased tissue degradation and propagation ...of inflammation whereas alternative polarization within a Th2 cytokine environment is associated with wound healing and angiogenesis. To understand if polarization of macrophages can lead to a procoagulant macrophage subset we polarized human monocyte derived macrophages to a proinflammatory and an alternative activation state. Alternative polarization with interleukin-4 and IL-13 led to a macrophage phenotype characterized by increased tissue factor (TF) production and release and by an increase in extracellular vesicle production. In addition, also TF activity was enhanced in extracellular vesicles of alternatively polarized macrophages. This TF induction was dependent on signal transducer and activator of transcription-6 signaling and poly ADP ribose polymerase activity. In contrast to monocytes, human macrophages did not show increased tissue factor expression upon stimulation with lipopolysaccharide and interferon-γ. Previous polarization to either a proinflammatory or an alternative activation subset does not change the subsequent stimulation of TF. The inability of proinflammatory activated macrophages to respond to lipopolysaccharide and interferon-γ with an increase in TF production seems to be due to an increase in TF promoter methylation and was reversible when treating these macrophages with a demethylation agent. In conclusion, we provide evidence that proinflammatory polarization of macrophages does not lead to enhanced procoagulatory function, whereas alternative polarization of macrophages leads to an increased expression of TF and increased production of TF bearing extracellular vesicles by these cells suggesting a procoagulatory phenotype of alternatively polarized macrophages.
Endothelial cells (ECs) are major modulators of hemostasis by expressing and releasing pro- and anticoagulant mediators into the circulation. Previous studies showed that cultured ECs release ...procoagulant mediators into cell culture supernatants as evidenced by the reduction of viscoelastic clotting time. This effect was reversed with an anti-tissue factor antibody. Here, we aimed to investigate whether tissue factor (TF) was released by endothelial-derived extracellular vesicles (EVs) and which portion of the released vesicles displays the most prominent procoagulant properties. After stimulation of ECs with tumor-necrosis factor-α (TNF-α) the supernatants of EC cultures were subjected to differential centrifugation steps to collect larger and smaller EVs which were then characterised by nanoparticle tracking analysis (NTA) and flow cytometry. Mixed with fresh human blood and analysed by thromboelastometry EVs exerted a significant procoagulant stimulus, which could be partly reversed by addition of an anti-TF antibody. Moreover, TF activity was confirmed in the centrifuged fractions. In summary, our results provide evidence of the procoagulant potential of smaller and larger endothelial-derived EV fractions detected by thromboelastometry. The observed effect is most likely due to the release of TF-bearing EVs of different dimensions, which are released upon TNF-α stimulation of endothelial cell cultures.
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