Macrophage Functions in Psoriasis: Lessons from Mouse Models.

Psoriasis is a systemic autoimmune/autoinflammatory disease that can be well studied in established mouse models. Skin-resident macrophages are classified into epidermal Langerhans cells and dermal macrophages and are involved in innate immunity, orchestration of adaptive immunity, and maintenance of tissue homeostasis due to their ability to constantly shift their phenotype and adapt to the current microenvironment. Consequently, both macrophage populations play dual roles in psoriasis. In some circumstances, pro-inflammatory activated macrophages and Langerhans cells trigger psoriatic inflammation, while in other cases their anti-inflammatory stimulation results in amelioration of the disease. These features make macrophages interesting candidates for modern therapeutic strategies. Owing to the significant progress in knowledge, our review article summarizes current achievements and indicates future research directions to better understand the function of macrophages in psoriasis.

Sex-specific associations between the environmental exposures and low-grade inflammation and increased blood pressure in young, healthy subjects.

Long-term exposures to environmental factors including airborne as well as noise pollutants, are associated with cardiovascular risk. However, the influence of environmental pollution on the young population is controversial. Accordingly, we aimed to investigate the relationships between long-term exposures to different environmental factors and major cardiovascular and inflammatory parameters and biomarkers in young, healthy subjects. Representative sample of permanent residents of two cities differing in air and noise pollution levels, aged 15-21 years, were recruited. Krakow and Lublin, both located in southern Poland, were chosen in relation to their similarities in demographic and geopolitical characteristics, but differences in air pollution (higher in Krakow) and noise parameters (higher in Lublin). A total of 576 subjects were studied: 292 in Krakow and 284 in Lublin. All subjects underwent health questionnaire, blood pressure measurements and biomarker determinations. Inflammatory biomarkers, such as CRP, hs-CRP, fibrinogen as well as homocysteine were all significantly higher in subjects living in Krakow as opposed to subjects living in Lublin (for hsCRP: 0.52 (0.32-0.98) mg/l vs. 0.35 (0.22-0.67) mg/l; p < 0.001). Increased inflammatory biomarker levels were observed in Krakow in both male and female young adults. Interestingly, significant differences were observed in blood pressure between male and female subjects. Males from Krakow had significantly higher mean systolic blood pressure (127.7 ± 10.4 mm/Hg vs. 122.4 ± 13.0 mm/Hg; p = 0.001), pulse pressure (58.7 ± 8.9 mm/Hg vs. 51.4 ± 12.3 mm/Hg; p < 0.001) and lower heart rate (p < 0.001) as compared to males living in Lublin. This was not observed in young adult females. Long-term exposure to environmental factors related to the place of residence can significantly influence inflammatory and cardiovascular parameters, even in young individuals. Interestingly, among otherwise healthy young adults, blood pressure differences exhibited significant variations based on biological sex.

Hypotensive drugs mitigate the high-sodium diet-induced pro-inflammatory activation of mouse macrophages in vivo.

Nowadays, there is an increasing emphasis on the need to alleviate the chronic inflammatory response to effectively treat hypertension. However, there are still gaps in our understanding on how to achieve this. Therefore, research on interaction of antihypertensive drugs with the immune system is extremely interesting, since their therapeutic effect could partly result from amelioration of hypertension-related inflammation, in which macrophages seem to play a pivotal role. Thus, current comprehensive studies have investigated the impact of repeatedly administered hypotensive drugs (captopril, olmesartan, propranolol, carvedilol, amlodipine, verapamil) on macrophage functions in the innate and adaptive immunity, as well as if drug-induced effects are affected by a high-sodium diet (HSD), one of the key environmental risk factors of hypertension. Although the assayed medications increased the generation of reactive oxygen and nitrogen intermediates by macrophages from standard fed donors, they reversed HSD-induced enhancing effects on macrophage oxidative burst and secretion of pro-inflammatory cytokines. On the other hand, some drugs increased macrophage phagocytic activity and the expression of surface markers involved in antigen presentation, which translated into enhanced macrophage ability to activate B cells for antibody production. Moreover, the assayed medications augmented macrophage function and the effector phase of contact hypersensitivity reaction, but suppressed the sensitization phase of cell-mediated hypersensitivity under HSD conditions. Our current findings contribute to the recognition of mechanisms, by which excessive sodium intake affects macrophage immune activity in hypertensive individuals, and provide evidence that the assayed medications mitigate most of the HSD-induced adverse effects, suggesting their additional protective therapeutic activity.

Immunomodulation by tramadol combined with acetaminophen or dexketoprofen: In vivo animal study.

Among other functions, macrophages remove foreign particles, including medications, from the circulation, making them an important target for immunomodulatory molecules. Currently, growing evidence suggests that analgesics affect the activity of immune cells not directly related to pain, and thus may induce unwanted immunosuppression in patients at risk. However, the immunomodulatory effects resulting from macrophage targeting by these drugs are understudied. Therefore, the current study investigated the immune effects induced in healthy mice by repeated administration of tramadol alone or in combination with acetaminophen or dexketoprofen. We observed that drug administration decreased the percentage of infiltrating macrophages in favor of resident macrophages in peritoneal exudates. While all drugs reduced the number of infiltrating macrophages that phagocytosed sheep red blood cells (SRBC), their administration increased the effectiveness of phagocytosis, and treatment with acetaminophen with or without tramadol elevated the expression of MHC class II by Mac3+ macrophages. Interestingly, SRBC-pulsed macrophages from mice treated with tramadol combined with acetaminophen potently activated SRBC-specific B cells in humoral response, and administration of these drugs to recipients of contact hypersensitivity effector cells augmented the resulting cellular immune response. In addition, tramadol administered alone or with dexketoprofen enhanced the spontaneous release of pro-inflammatory cytokines by macrophages. Our current research findings demonstrate that tramadol therapy in combination with acetaminophen or dexketoprofen has a relatively low risk of causing immunosuppressive side effect because the drugs slightly reduce the inflammatory reaction of macrophages but do not impair their ability to activate the adaptive immune responses.

Overreactive macrophages in SARS-CoV-2 infection: The effects of ACEI.

Among various factors influencing the course of SARS-CoV-2 infection in humans, macrophage overactivation is considered the main cause of the cytokine storm that leads to severe complications of COVID-19. Moreover, the increased expression of angiotensin converting enzyme 2 (ACE2), an obligatory entry receptor of the coronavirus, caused by treatment with ACE inhibitors (ACEI) lowered overall confidence in the safety of these drugs. However, analysis of the course of coronavirus infection in patients treated with ACEI does not support these concerns. Instead, the beneficial effect of ACEI on macrophages has increasingly been emphasized. This includes their anti-inflammatory activation and the consequent reduction in the risk of severe disease and life-threatening complications. Herein, we summarize the current knowledge and understanding of the dual role of macrophages in SARS-CoV-2 infection, with a special focus on the postulated mechanisms underlying the beneficial effects of macrophage targeting by ACEI. These seem to involve the stimulation of macrophage angiotensin II type 2 and Mas receptors by angiotensin 1-7, intensively produced due to the up-regulation of ACE2 expression on macrophages, as well as the direct inhibition of macrophage hyper-responsiveness by ACEI. The impact of ACEI on macrophages may also lead to the activation of an effective antiviral response due to the increased expression of ACE2.

Biodelivery of therapeutic extracellular vesicles: should mononuclear phagocytes always be feared?

At present, extracellular vesicles (EVs) are considered key candidates for cell-free therapies, including treatment of allergic and autoimmune diseases. However, their therapeutic effectiveness, dependent on proper targeting to the desired cells, is significantly limited due to the reduced bioavailability resulting from their rapid clearance by the cells of the mononuclear phagocyte system (MPS). Thus, developing strategies to avoid EV elimination is essential when applying them in clinical practice. On the other hand, malfunctioning MPS contributes to various immune-related pathologies. Therapeutic reversal of these effects with EVs would be beneficial and could be achieved, for example, by modulating the macrophage phenotype or regulating antigen presentation by dendritic cells. Additionally, intended targeting of EVs to MPS macrophages for replication and repackaging of their molecules into new vesicle subtype can allow for their specific targeting to appropriate populations of acceptor cells. Herein, we briefly discuss the under-explored aspects of the MPS-EV interactions that undoubtedly require further research in order to accelerate the therapeutic use of EVs.

Layered plaque and plaque volume in patients with acute coronary syndromes.

BACKGROUND: Layered plaque is a signature of previous subclinical plaque destabilization and healing. Following plaque disruption, thrombus becomes organized, resulting in creation of a new layer, which might contribute to rapid step-wise progression of the plaque. However, the relationship between layered plaque and plaque volume has not been fully elucidated. METHODS: Patients who presented with acute coronary syndromes (ACS) and underwent pre-intervention optical coherence tomography (OCT) and intravascular ultrasound (IVUS) imaging of the culprit lesion were included. Layered plaque was identified by OCT, and plaque volume around the culprit lesion was measured by IVUS. RESULTS: Among 150 patients (52 with layered plaque; 98 non-layered plaque), total atheroma volume (183.3 mm3[114.2 mm3 to 275.0 mm3] vs. 119.3 mm3[68.9 mm3 to 185.5 mm3], p = 0.004), percent atheroma volume (PAV) (60.1%[54.7-60.1%] vs. 53.7%[46.8-60.6%], p = 0.001), and plaque burden (86.5%[81.7-85.7%] vs. 82.6%[77.9-85.4%], p = 0.001) were significantly greater in patients with layered plaques than in those with non-layered plaques. When layered plaques were divided into multi-layered or single-layered plaques, PAV was significantly greater in patients with multi-layered plaques than in those with single-layered plaques (62.1%[56.8-67.8%] vs. 57.5%[48.9-60.1%], p = 0.017). Layered plaques, compared to those with non-layered pattern, had larger lipid index (1958.0[420.9 to 2502.9] vs. 597.2[169.1 to 1624.7], p = 0.014). CONCLUSION: Layered plaques, compared to non-layered plaques, had significantly greater plaque volume and lipid index. These results indicate that plaque disruption and the subsequent healing process significantly contribute to plaque progression at the culprit lesion in patients with ACS. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov , NCT01110538, NCT03479723, UMIN000041692.

Advances in the Current Understanding of the Role of Extracellular Vesicles in Allergy, Autoimmunity and Immune Regulation.

Cells release extracellular vesicles (EVs), such as exosomes and microvesicles, both under physiological and pathological conditions, making EV-dependent signaling cascades a very precise system of intercellular communication [...].

Intracoronary Imaging of Vulnerable Plaque-From Clinical Research to Everyday Practice.

The introduction into clinical practice of intravascular imaging, including intravascular ultrasound (IVUS), optical coherence tomography (OCT) and their derivatives, allowed for the in vivo assessment of coronary atherosclerosis in humans, including insights into plaque evolution and progression process. Intravascular ultrasound, the most commonly used intravascular modality in many countries, due to its low resolution cannot assess many features of vulnerable plaque such as lipid plaque or thin-cap fibroatheroma. Thus, novel methods were introduced to facilitate this problem including virtual histology intravascular ultrasound and later on near-infrared spectroscopy and OCT. Howbeit, none of the currently used modalities can assess all known characteristics of plaque vulnerability; hence, the idea of combining different intravascular imaging methods has emerged including NIRS-IVUS or OCT-IVUS imaging. All of those described methods may allow us to identify the most vulnerable plaques, which are prone to cause acute coronary syndrome, and thus they may allow us to introduce proper treatment before plaque destabilization.

The impact of the COVID-19 pandemic on job satisfaction among professionally active nurses in five European countries.

The COVID-19 pandemic has negatively affected the work of many medical professionals, including the group of nurses. This study aimed at assessing the impact of the COVID-19 pandemic on job satisfaction of nursing staff in five European countries. The study was conducted using the Job Satisfaction Scale (SSP) and original questions on the job satisfaction. The cross-sectional online study was conducted with a sample of 1,012 professionally active nurses working in Poland, Germany, Italy, Great Britain and Sweden, who assessed their job satisfaction before (retrospectively) and during the pandemic. The results showed a significant decrease in job satisfaction due to the need to perform it during the pandemic caused by the SARS-CoV-2 virus. In 8 out of 10 examined parameters of job satisfaction, a statistically significant decrease in job satisfaction was observed at the level of p < 0.05. Among the examined factors influencing job satisfaction, the highest decrease was recorded based on the assessment of working conditions (1,480). A high level of satisfaction with the work of nurses has a significant impact on providing better patient care as well as reducing the risk of professional burnout of nurses.

Clinical Characteristics Predicting Worse Long-Term Outcomes in Patients with Myocardial Infarction and Non-Obstructive Coronary Arteries (MINOCA).

Non-obstructive coronary artery disease occurs in 3.5-15% of patients presenting with acute myocardial infarction. This group of patients has a poor prognosis. Identification of factors that predict worse outcomes in myocardial infarction with non-obstructive coronary arteries (MINOCA) is therefore important. Patients with a diagnosis of MINOCA (n = 110) were enrolled in this single-center, retrospective registry. Follow-up was performed 12, 24 and 36 months after discharge. The primary composite endpoint was defined as myocardial infarction, coronary revascularization, stroke or TIA, all-cause death, or hospital readmission due to any cardiovascular event. The mean age of the study group was 64.9 (± 13.5) years and 38.2% of patients were male. The occurrence of the primary composite endpoint was 36.4%. In a COX proportional hazards model analysis, older age (p = 0.027), type 2 diabetes (p = 0.013), history of neoplasm (p = 0.004), ST-segment depression (p = 0.018) and left bundle branch block/right bundle branch block (p = 0.004) by ECG on discharge, higher Gensini score (p = 0.022), higher intraventricular septum (p = 0.007) and posterior wall thickness increases (p = 0.001) were shown to be risk factors for primary composite endpoint occurrence. Our study revealed that several factors such as older age, type 2 diabetes, ST-segment depression and LBBB/RBBB in ECG on discharge, higher Gensini score, and myocardial hypertrophy and history of neoplasm may contribute to worse clinical outcomes in MINOCA patients.

Extracellular Vesicles-Oral Therapeutics of the Future.

Considered an artifact just after discovery, the possibility of oral delivery of extracellular vesicles (EVs) and their functional cargos has recently gained much research attention. EVs from various sources, including edible plants, milk, bacteria and mammalian cells, have emerged as a platform for miRNA and drug delivery that seem to induce the expected immune effects locally and in distant tissues after oral administration. Such a possibility greatly expands the clinical applicability of EVs. The present review summarizes research findings that either support or deny the biological/therapeutical activity of orally administered EVs and their role in cross-species and cross-kingdom signaling.

Procedural Outcomes in Patients Treated with Percutaneous Coronary Interventions within Chronic Total Occlusions Stratified by Gender.

It has been demonstrated that gender differences are related to different procedural and long-term clinical outcomes among a general patient population treated using percutaneous coronary interventions (PCI). The objective of our analysis was to conduct assessment regarding the relationship between gender and procedural outcomes in patients treated for PCI regarding chronic total occlusions (CTO), based on a large, real-life registry. Data used to conduct the following analysis was derived from the national registry of percutaneous coronary interventions (ORPKI), upheld in co-operation with the Association of Cardiovascular Interventions (AISN) of the Polish Cardiac Society. The study involved data procured from the registry within the period from January 2014 to December 2020. All subsequent CTO procedures recorded in the registry during that period were included in the analysis. We assessed the correlation between gender and the overall rate of periprocedural complications, procedure-related mortality, and success evaluated as TIMI flow grade 3 after the procedure by univariate and multivariable modeling. At the time of conducting our investigation, there were 162 existing and active CathLabs, at which 747,033 PCI procedures were carried out during the observational period. Of those, 14,903 (1.99%) were CTO-PCI procedures, and 3726 were women (25%). The percentage share between genders did not experience any significant changes during the consecutive years observed in the current analysis. Overall periprocedural complication rate was greater among women than men (3.45% vs. 2.31%, p = 0.02). A comparable relationship was noted for procedural mortality (0.7% vs. 0.2%, p = 0.006), while procedural success occurred more often in the case of women (69.3% vs. 65.2%, p < 0.001). Women were found to be more frequently affected by periprocedural complications (OR = 1.553; 95%CI: 1.212−1.99, p < 0.001) as well as procedural success (OR = 1.294; 95%CI: 1.151−1.454, p < 0.001), evaluated using multivariable models. Based on the current analysis performed on all-comer patients treated using PCI in CTO, women are affected by more frequent procedural complication occurrence as well as greater procedural success compared to men.

PRECISE-DAPT score for bleeding risk prediction in patients on dual or single antiplatelet regimens: insights from the GLOBAL LEADERS and GLASSY.

AIMS: The five-item PRECISE-DAPT, integrating age, haemoglobin, white-blood-cell count, creatinine clearance, and prior bleeding, predicts bleeding risk in patients on dual antiplatelet therapy (DAPT) after stent implantation. We sought to assess whether the bleeding risk prediction offered by the PRECISE-DAPT remains valid among patients receiving ticagrelor monotherapy from 1 month onwards after coronary stenting instead of standard DAPT and having or not having centrally adjudicated bleeding endpoints. METHODS AND RESULTS: The PRECISE-DAPT was calculated in 14 928 and 7134 patients from GLOBAL LEADERS and GLASSY trials, respectively. The ability of the score to predict Bleeding Academic Research Consortium 3 or 5 bleeding was assessed and compared among patients on ticagrelor monotherapy (experimental strategy) or standard DAPT (reference strategy) from 1 month after drug-eluting stent implantation. Bleeding endpoints were investigator-reported or centrally adjudicated in GLOBAL LEADERS and GLASSY, respectively. At 2 years, the c-indexes for the score among patients treated with the experimental or reference strategy were 0.67 [95% confidence interval (CI): 0.63-0.71] vs. 0.63 (95% CI: 0.59-0.67) in GLOBAL LEADERS (P = 0.27), and 0.67 (95% CI: 0.61-0.73) vs. 0.66 (95% CI: 0.61-0.72) in GLASSY (P = 0.88). Decision curve analysis showed net benefit using the PRECISE-DAPT to guide bleeding risk assessment under both treatment strategies. Results were consistent between investigator-reported and adjudicated endpoints and using the simplified four-item PRECISE-DAPT. CONCLUSION: The PRECISE-DAPT offers a prediction model that proved similarly effective to predict clinically relevant bleeding among patients on ticagrelor monotherapy from 1 month after coronary stenting compared with standard DAPT and appears to be unaffected by the presence or absence of adjudicated bleeding endpoints.

Increasing the Therapeutic Efficacy of Extracellular Vesicles From the Antigen-Specific Antibody and Light Chain Perspective.

Due to their exceptional properties, extracellular vesicles (EVs) receive special attention as next generation biotherapeutics and vehicles for drug delivery. However, despite having many advantages over cell-based therapies, EVs usually exert lower therapeutic efficacy. This results from a number of hurdles that are faced by the EV-based approaches. Administered EVs could be rapidly cleared by the mononuclear phagocytes as well as can randomly distribute within various tissues, making tissue penetration and cell targeting insufficient. However, recent research findings imply that these limitations could be overcome with the use of antigen-specific antibodies and light chains. Major histocompatibility complex (MHC) class II-expressing EVs have been shown to form aggregates after co-incubation with antigen-specific antibodies, which greatly enhanced their biological efficacy. On the other hand, EVs could be coated with antibody light chains of chosen specificity to direct them towards desired target cell population. Both findings open up a promising perspective to achieve the highest efficacy of the EV-based approaches. Herein we discuss the opportunities for enhancing extracellular vesicle's biological activity by using specific antibodies and light chains in the context of the challenges faced by such therapeutic approach.

Predictors and trends of contrast use and radiation exposure in a large cohort of patients treated with percutaneous coronary interventions: Chronic total occlusion analysis based on a national registry.

BACKGROUND: The aim herein, was to assess predictors and current trends of radiation exposure and total contrast amount use in patients treated with percutaneous coronary intervention within chronic total occlusion (CTO PCI) and non-CTO PCI. METHODS: Based on a nationwide registry (ORPKI), 535,857 patients treated with PCI between 2014 and 2018 were analysed. The study included 12,572 (2.34%) patients treated with CTO PCI. The CTO PCI and non-CTO PCI groups were compared before and after propensity score matching (PSM). Multifactorial mixed regression models were used to assess predictors of contrast amount use and radiation exposure. RESULTS: The mean total contrast dose and radiation exposure decrease reached statistical significance in following years for the CTO PCI (p = 0.002 and p < 0.001) and non-CTO PCI groups (p < 0.001 and p < 0.001). Multifactorial analysis revealed that non-CTO PCI was a strong independent predictor of lower total contrast dose (estimate: -17.41; 95% confidence interval [CI]: -18.45 to -16.49, p < 0.001) and radiation exposure (estimate: -264.28; 95% CI: -273.75 to -254.81, p < 0.001). After PSM, it was confirmed that CTO PCI was an independent predictor of greater radiation exposure (estimate: 328.6; 95% CI: 289.1-368.1; p < 0.001) and total contrast dose (estimate: 30.5; 95% CI: 27.28-33.74; p < 0.001). CONCLUSIONS: Contrast dose and radiation exposure have decreased in previous years with regard to the CTO PCI and non-CTO PCI groups. CTO PCI was found to be an independent predictor of greater total contrast dose and radiation exposure in the overall group of patients treated with PCI.

Coronary plaque and clinical characteristics of South Asian (Indian) patients with acute coronary syndromes: An optical coherence tomography study.

BACKGROUND: South Asians, and Indians in particular, are known to have a higher incidence of premature atherosclerosis and acute coronary syndromes (ACS) with worse clinical outcomes, compared to populations with different ethnic backgrounds. However, the underlying pathobiology accounting for these differences has not been fully elucidated. METHODS: ACS patients who had culprit lesion optical coherence tomography (OCT) imaging were enrolled. Culprit plaque characteristics were evaluated using OCT. RESULTS: Among 1315 patients, 100 were South Asian, 1009 were East Asian, and 206 were White. South Asian patients were younger (South Asians vs. East Asians vs. Whites: 51.6 ± 13.4 vs. 65.4 ± 11.9 vs. 62.7 ± 11.7; p < 0.001) and more frequently presented with ST-segment elevation myocardial infarction (STEMI) (77.0% vs. 56.4% vs. 35.4%; p < 0.001). On OCT analysis after propensity group matching, plaque erosion was more frequent (57.0% vs. 38.0% vs. 50.0%; p = 0.003), the lipid index was significantly greater (2281.6 [1570.8-3160.6] vs. 1624.3 [940.9-2352.4] vs. 1303.8 [1090.0-1757.7]; p < 0.001), and the prevalence of layered plaque was significantly higher in the South Asian group than in the other two groups (52.0% vs. 30.0% vs. 34.0%; p = 0.003). CONCLUSIONS: Compared to East Asians and Whites, South Asians with ACS were younger and more frequently presented with STEMI. Plaque erosion was the predominant pathology for ACS in South Asians and their culprit lesions had more features of plaque vulnerability. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov, NCT03479723.

Antibodies Enhance the Suppressive Activity of Extracellular Vesicles in Mouse Delayed-Type Hypersensitivity.

Previously, we showed that mouse delayed-type hypersensitivity (DTH) can be antigen-specifically downregulated by suppressor T cell-derived miRNA-150 carried by extracellular vesicles (EVs) that target antigen-presenting macrophages. However, the exact mechanism of the suppressive action of miRNA-150-targeted macrophages on effector T cells remained unclear, and our current studies aimed to investigate it. By employing the DTH mouse model, we showed that effector T cells were inhibited by macrophage-released EVs in a miRNA-150-dependent manner. This effect was enhanced by the pre-incubation of EVs with antigen-specific antibodies. Their specific binding to MHC class II-expressing EVs was proved in flow cytometry and ELISA-based experiments. Furthermore, by the use of nanoparticle tracking analysis and transmission electron microscopy, we found that the incubation of macrophage-released EVs with antigen-specific antibodies resulted in EVs' aggregation, which significantly enhanced their suppressive activity in vivo. Nowadays, it is increasingly evident that EVs play an exceptional role in intercellular communication and selective cargo transfer, and thus are considered promising candidates for therapeutic usage. However, EVs appear to be less effective than their parental cells. In this context, our current studies provide evidence that antigen-specific antibodies can be easily used for increasing EVs' biological activity, which has great therapeutic potential.