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Atherosclerosis is a chronic lipid-driven inflammatory disease characterized by infiltration of large numbers of macrophages. The progression of the disease is closely related to the status of macrophages in atherosclerotic plaques. Recent advances in plaque analysis have revealed a subpopulation of macrophages that express high levels of triggering receptor expressed on myeloid cells 2 (TREM2). Although TREM2 is known to play a critical role in inflammation, lipid metabolism, and tissue repair, its role in atherosclerosis is still not fully understood. Recent studies have shown that TREM2 promotes macrophage cholesterol uptake and efflux, enhances efferocytosis function, regulates inflammation and metabolism, and promotes cell survival, all of which are significant functions in atherosclerosis. In early plaques TREM2 promotes lipid uptake and increases lesion size. In advanced plaques TREM2 promotes macrophage survival and increases plaque stability. The dualistic nature of TREM2 in atherosclerosis, where it can exert both protective effect and a side effect of increased lesion size, presents a complex but crucial area of study. Understanding these dual roles could help in the development of new therapeutic strategies to modulate TREM2 activity and utilize its atheroprotective function while mitigating its deleterious effects. In this review, we discuss the roles and mechanisms of TREM2 during different stages of atherosclerotic plaques, as well as the potential applications of TREM2 in the diagnosis and treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Atherosclerosis serves as the primary catalyst for numerous cardiovascular diseases. Growing evidence suggests that the immune response is involved in every stage of atherosclerotic plaque evolution. Rapid, but not specific, innate immune arms, including neutrophils, monocytes/macrophages, dendritic cells (DCs) and other innate immune cells, as well as pattern-recognition receptors and various inflammatory mediators, contribute to atherogenesis. The specific adaptive immune response, governed by T cells and B cells, antibodies, and immunomodulatory cytokines potently regulates disease activity and progression. In the inflammatory microenvironment, the heterogeneity of leukocyte subpopulations plays a very important regulatory role in plaque evolution. With advances in experimental techniques, the fine mechanisms of immune system involvement in atherosclerotic plaque evolution are becoming known. In this review, we examine the critical immune responses involved in atherosclerotic plaque evolution, in particular, looking at atherosclerosis from the perspective of evolutionary immunobiology. A comprehensive understanding of the interplay between plaque evolution and plaque immunity provides clues for strategically combating atherosclerosis. [ABSTRACT FROM AUTHOR]

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by antinuclear antibody production, which has been linked to an excess of apoptotic cells, normally eliminated by macrophages through efferocytosis. Additionally, circulating levels of CXCL4, a novel SSc biomarker, correlate with more severe fibrotic manifestations of the disease. Considering the defective efferocytosis of macrophages in SSc and the CXCL4-related M4 macrophage phenotype, we hypothesized that CXCL4 could be involved in the alteration of phagocytic functions of macrophages in SSc, including LC3-associated phagocytosis (LAP), another phagocytic process requiring autophagy proteins and contributing to immune silencing. Methods: In this study, CXCL4 levels were measured by ELISA in vitro in the serum of SSc patients, and also in vivo in the serum and lungs of C57BL/6J SSc mice induced by intradermal injections of hypochloric acid (HOCl) or Bleomycin (BLM), with evaluation of M4 markers. Circulating monocytes from healthy donors were also differentiated in vitro into M4 monocytes-derived macrophages (MDMs) in the presence of recombinant CXCL4. In M4-MDMs, phagocytosis of fluorescent beads and expression level of efferocytic receptors were evaluated by flow cytometry in vitro, while efferocytosis of pHrodo-stained apoptotic Jurkat cells was evaluated by real-time fluorescence microscopy. LAP quantification was made by fluorescence microscopy in M4-MDMs exposed to IgG-coated beads as well as apoptotic Jurkat cells. Results: Our results demonstrated that efferocytosis was significantly reduced in M0-MDMs from healthy donors exposed to the CXCL4-rich plasma of SSc patients. In vivo, CXCL4 expression was increased in the lungs of both SScmouse models, along with elevated M4 markers, while efferocytosis of BLM-mice alveolar macrophages was decreased. In vitro, M4-MDMs exhibited reduced efferocytosis compared to M0-MDMs, notably attributable to lower CD36 receptor expression and impaired phagocytosis capacities, despite enhanced LAP. Autophagic gene expression was increased both in vitro in SSc MDMs and in vivo in BLM mice, thus acting as a potential compensatory mechanism. Discussion: Altogether, our results support the role of CXCL4 on the impaired efferocytosis capacities of human macrophages from SSc patients and in SSc mice. [ABSTRACT FROM AUTHOR]

Macrophage polarization is an important phenomenon that underlies various physiological mechanisms protective to the host and pathological mechanisms manipulated by microbes, thus we need to come to terms with this phenomenon and understand it at the molecular level. This paper highlights various aspects of macrophage activation and polarization starting from the discovery of macrophages to the latest advancements like using algorithms to determine polarization in a marker-free manner. We have covered macrophage polarization in response to various stimuli and also how this is affected in various disease conditions. Macrophage polarization in many neurodegenerative diseases has also been covered in this review. Various methods used for detecting and quantifying this phenomenon have been discussed below. It has been noted that our understanding of this phenomenon may lead to many novel therapeutic approaches in dealing with a varied set of disease pathologies making it extremely valuable for clinical practice. Newer technological advancements in the field have the potential to act as diagnostic tools for various diseases. In this paper, we have tried to summarize the existing information on macrophage polarization and activation to understand the progress we have made in understanding this phenomenon. Highlights: History of macrophage activation and polarization have been discussed. Various metabolic pathways that underline the functions of polarized macrophages has been discussed. Macrophage polarization in response to various stimuli in the microenvironment has been discussed including the newer discovered M4 macrophage state. Macrophage polarization in response to various disease pathologies like neurodegenerative diseases, mycobacterial diseases, plaque, HIV and other disease has been highlighted. Different methods for describing macrophage polarization have been discussed including newer methods using algorithms and machine learning. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a chronic inflammatory condition primarily affecting large and medium arteries, is the main cause of cardiovascular diseases. Macrophages are key mediators of inflammatory responses. They are involved in all stages of atherosclerosis development and progression, from plaque formation to transition into vulnerable plaques, and are considered important therapeutic targets. Increasing evidence suggests that the modulation of macrophage polarization can effectively control the progression of atherosclerosis. Herein, we explore the role of macrophage polarization in the progression of atherosclerosis and summarize emerging therapies for the regulation of macrophage polarization. Thus, the aim is to inspire new avenues of research in disease mechanisms and clinical prevention and treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Heterogeneity describes the differences among cancer cells within and between tumors. It refers to cancer cells describing variations in morphology, transcriptional profiles, metabolism, and metastatic potential. More recently, the field has included the characterization of the tumor immune microenvironment and the depiction of the dynamics underlying the cellular interactions promoting the tumor ecosystem evolution. Heterogeneity has been found in most tumors representing one of the most challenging behaviors in cancer ecosystems. As one of the critical factors impairing the long-term efficacy of solid tumor therapy, heterogeneity leads to tumor resistance, more aggressive metastasizing, and recurrence. We review the role of the main models and the emerging single-cell and spatial genomic technologies in our understanding of tumor heterogeneity, its contribution to lethal cancer outcomes, and the physiological challenges to consider in designing cancer therapies. We highlight how tumor cells dynamically evolve because of the interactions within the tumor immune microenvironment and how to leverage this to unleash immune recognition through immunotherapy. A multidisciplinary approach grounded in novel bioinformatic and computational tools will allow reaching the integrated, multilayered knowledge of tumor heterogeneity required to implement personalized, more efficient therapies urgently required for cancer patients. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages are effector cells and accumulate to the damaged and inflamed sites of arteries to internalize native and chemically modified lipoproteins to transform them into cholesterol-loaded foam cells. Foam cell formation is determined by the capacity of phagocytosis, migration, scavenging, and the features of phenotypes. Macrophages are diverse, and the subsets and functions are controlled by their surrounding microenvironment. Generally, macrophages are divided into classically activated (M1) and alternatively activated (M2). Recently, intraplaque macrophage phenotypes are recognized by the stimulation of CXCL4 (M4), oxidized phospholipids (Mox), hemoglobin/haptoglobin complexes [HA-mac/M(Hb)], and heme (Mhem). The pro-atherogenic or anti-atherosclerotic phenotypes of macrophages decide the progression of AS. Besides, apoptosis, necrosis, ferroptosis, autophagy and pyrotopsis determine plaque formation and cardiovascular vulnerability, which may be associated with macrophage polarization phenotypes. In this review, we first summarize the three most popular hypotheses for AS and find the common key factors for further discussion. Secondly, we discuss the factors affecting macrophage polarization and five types of macrophage death in AS progression, especially ferroptosis. A comprehensive understanding of the cellular and molecular mechanisms of plaque formation is conducive to disentangling the candidate targets of macrophage-targeting therapies for clinical intervention at various stages of AS. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is one of the most common complications of cardiovascular diseases (CVDs) and among the leading causes of death in the US. Many other CVDs can lead to increased mortality as well. Investigating the genetic epidemiology and susceptibility to CVDs is a central focus of cardiology and biomedical life sciences. Several studies have explored expression of key CVD genes specially in HF, yet new targets and biomarkers for early diagnosis are still missing to support personalized treatment. Lack of gender-specific cardiac biomarker thresholds in men and women may be the reason for CVD underdiagnosis in women, and potentially increased morbidity and mortality as a result, or conversely, an overdiagnosis in men. In this context, it is important to analyze the expression and enrichment of genes with associated phenotypes and disease-causing variants among high-risk CVD populations. Methods: We performed RNA sequencing focusing on key CVD genes with a great number of genetic associations to HF. Peripheral blood samples were collected from a broad age range of adult male and female CVD patients. These patients were clinically diagnosed with CVDs and CMS/HCC HF, as well as including cardiomyopathy, hypertension, obesity, diabetes, asthma, high cholesterol, hernia, chronic kidney, joint pain, dizziness and giddiness, osteopenia of multiple sites, chest pain, osteoarthritis, and other diseases. Results: We report RNA-seq driven case–control study to analyze patterns of expression in genes and differentiating the pathways, which differ between healthy and diseased patients. Our in-depth gene expression and enrichment analysis of RNA-seq data from patients with mostly HF and other CVDs on differentially expressed genes and CVD annotated genes revealed 4,885 differentially expressed genes (DEGs) and regulation of 41 genes known for HF and 23 genes related to other CVDs, with 15 DEGs as significantly expressed including four genes already known (FLNA, CST3, LGALS3, and HBA1) for HF and CVDs with the enrichment of many pathways. Furthermore, gender and ethnic group specific analysis showed shared and unique genes between the genders, and among different races. Broadening the scope of the results in clinical settings, we have linked the CVD genes with ICD codes. Conclusions: Many pathways were found to be enriched, and gender-specific analysis showed shared and unique genes between the genders. Additional testing of these genes may lead to the development of new clinical tools to improve diagnosis and prognosis of CVD patients. [ABSTRACT FROM AUTHOR]

Background: Galectin-3-binding protein (GAL-3BP) is a ubiquitous and multifunctional secreted glycoprotein, which functions in innate immunity and has been highlighted as a potential mediator of adipose inflammation in obesity. In this study, we aimed to identify whether GAL-3BP is a novel biological marker for metabolic syndrome (MetS). Methods: The biochemical and anthropometric variables of the 570 participants in this study were evaluated using standard procedures. Their serum GAL-3BP levels were measured using enzyme-linked immunosorbent assay (ELISA), while the association between the glycoprotein and MetS was analyzed using multiple logistic regression analyses. Moreover, an experimental MetS model was established. The expression of GAL-3BP in serum and adipose tissue was measured using ELISA and western blotting. Lipid accumulation was determined with the use of immunohistochemistry and immunofluorescent staining. Results: The serum GAL-3BP level was found to be positively associated with MetS. The logistic regression analyses demonstrated that participants expressing the upper levels of GAL-3BP were more likely to develop MetS than those expressing less of the glycoprotein (OR = 2.39, 95%CI: 1.49, 3.83). The association between the serum GAL-3BP level and MetS was found preferentially in postmenopausal women (OR = 2.30, 95%CI: 1.31, 4.05). In addition, GAL-3BP was increased in the serum and visceral adipose tissue (VAT) of high fat diet (HFD) mice. Moreover, GAL-3BP was highly expressed in VAT macrophages. Conclusions: This study confirmed serum GAL-3BP to be positively associated with MetS, highlighting it as a useful biological marker of MetS in Chinese participants. [ABSTRACT FROM AUTHOR]

A choledochal cyst (CDC) is a rare congenital, single, or multiple cystic dilatations of the biliary tract encountered most commonly in infants and children. A sensitive and specific serological marker, if available, may add to its early recognition thereby avoiding the risk of complications frequently seen in these patients. We analyzed serum galectin-3-binding protein (Gal-3BP) levels in 21 children with CDC and 14 age-matched controls by the ELISA method. Serum Gal-3-BP levels were significantly raised in the patient group (36.6 ±25.2 ng/ml versus 7.0 ±4.3 ng/ml in controls; p <0.0001) and 95.2% of patients had Gal-3BP levels higher than the mean value in controls. Almost 67% of patients showed values ≥3 times of mean Gal-3BP level in controls (p <0.0001). Equal to 5 times or greater levels were seen in 43% of the patients (p = 0.0051). The study, therefore, suggests further evaluation of Gal-3BP as a potential biomarker for CDC and other biliary disorders. [ABSTRACT FROM AUTHOR]

Inflammatory diseases are an important health concern and have a growing incidence worldwide. Thus, developing novel and safe drugs to treat these disorders remains an important pursuit. Artemisia iwayomogi, locally known as Dowijigi (DJ), is a perennial herb found primarily in Korea and is used to treat various diseases such as hepatitis, inflammation and immune disorders. In the present study, the anti-inflammatory effects of a polyphenolic extract from the DJ flower (PDJ) in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW264.7 cells were investigated. Cell cytotoxicity was assessed using the MTT assay. The production of nitric oxide (NO) and prostaglandin E2 (PGE2) was measured by Griess and ELISA analysis, respectively. The expression levels of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX2) were examined by western blot analysis. Reverse transcription-quantitative PCR was performed to detect the mRNA expression levels of pro-inflammatory cytokines, including tumor necrosis factor α (TNFα), interleukin (IL)-6 and IL-1β, as well as COX2 and iNOS. The production of NO and PGE2 was significantly decreased following treatment with PDJ. The mRNA expression levels of TNFα, IL-6, IL-1β, COX2 and iNOS were significantly decreased in LPS-induced PDJ co-treated cells compared with the group treated with LPS alone. Western blot analysis indicated that PDJ downregulated the LPS-induced expression of iNOS and COX2, as well as the expression of NF-κB proteins. In conclusion, the present study demonstrated that PDJ exerted anti-inflammatory effects in LPS-induced macrophage cells by suppressing the NF-κB signaling pathway. Therefore, PDJ may be used as a potential therapeutic agent in inflammation. [ABSTRACT FROM AUTHOR]

Macrophages are a functionally heterogeneous group of cells with specialized functions depending not only on their subgroup but also on the function of the organ or tissue in which the cells are located. The concept of macrophage phenotypic heterogeneity has been investigated since the 1980s, and more recent studies have identified a diverse spectrum of phenotypic subpopulations. Several types of macrophages play a central role in the response to infectious agents and, along with other components of the immune system, determine the clinical outcome of major infectious diseases. Here, we review the functions of various macrophage phenotypic subpopulations, the concept of macrophage polarization, and the influence of these cells on the evolution of infections. In addition, we emphasize their role in the immune response in vivo and in situ, as well as the molecular effectors and signaling mechanisms used by these cells. Furthermore, we highlight the mechanisms of immune evasion triggered by infectious agents to counter the actions of macrophages and their consequences. Our aim here is to provide an overview of the role of macrophages in the pathogenesis of critical transmissible diseases and discuss how elucidation of this relationship could enhance our understanding of the host–pathogen association in organ-specific immune responses. [ABSTRACT FROM AUTHOR]

Background: Since macrophages are one of the major cell types involved in the Mycobacterium leprae immune response, roles of the M1 and M2 macrophage subpopulations have been well defined. However, the role of M4 macrophages in leprosy or other infectious diseases caused by mycobacteria has not yet been clearly characterized. This study aimed to investigate the presence and potential role of M4 macrophages in the immunopathology of leprosy.Methods: We analyzed the presence of M4 macrophage markers (CD68, MRP8, MMP7, IL-6, and TNF-α) in 33 leprosy skin lesion samples from 18 patients with tuberculoid leprosy and 15 with lepromatous leprosy by immunohistochemistry.Results: The M4 phenotype was more strongly expressed in patients with the lepromatous form of the disease, indicating that this subpopulation is less effective in the elimination of the bacillus and consequently is associated with the evolution to one of the multibacillary clinical forms of infection.Conclusion: M4 macrophages are one of the cell types involved in the microbial response to M. leprae and probably are less effective in controlling bacillus replication, contributing to the evolution to the lepromatous form of the disease. [ABSTRACT FROM AUTHOR]

The S100 protein family is widely involved in the pathological process of various types of cancer. However, the prognostic value of the S100 protein family member S100A12 in hepatocellular carcinoma (HCC) remains unknown. A total of 139 patients undergoing curative surgical resection for HCC from December 2005 to June 2006 were investigated. Immunohistochemistry of S100A12 tissue was performed and expression was classified according to the total positive staining area. Co‑expression of S100A12 with cluster of differentiation (CD)11B, CD15 and CD68 was evaluated using immunofluorescence. Associations between S100A12 expression and preoperative clinicopathological parameters were assessed using a χ2 test or independent sample Student's t‑test. Kaplan‑Meier estimator survival analysis and multivariate Cox's proportional hazard regression model were used to evaluate the prognostic value of S100A12 expression. The expression of S100A12 was restricted exclusively to stroma cells, primarily to myeloid‑derived immune cells, CD15‑positive neutrophils and CD68‑positive macrophages in particular. A total positive staining area of 1,600 μm2 was selected as the threshold between high and low S100A12 expression. There was a statistically significant association between intratumoral S100A12 expression and tumor differentiation (P=0.010). High expression of S100A12 on intratumoral stroma cells was an independent prognostic factor for the overall (P=0.002) and disease‑free survival (P=0.007) rates of HCC following curative surgical resection. No significant association was identified between peritumoral S100A12 expression and HCC prognosis. The results of the present study demonstrated that high expression of S100A12 on intratumoral stroma cells is associated with poor HCC prognosis following curative resection, which may serve as a potential target for an adjuvant therapy. [ABSTRACT FROM AUTHOR]

Macrophages represent a heterogeneous cell population and are known to display a remarkable plasticity. In response to distinct micro-environmental stimuli, e.g., tumor stroma vs. infected tissue, they polarize into different cell subtypes. Originally, two subpopulations were defined: classically activated macrophages or M1, and alternatively activated macrophages or M2. Nowadays, the M1/M2 classification is considered as an oversimplified approach that does not adequately cover the total spectrum of macrophage phenotypes observed in vivo. Especially in pathological circumstances, macrophages behave as plastic cells modifying their expression and transcription profile along a continuous spectrum with M1 and M2 phenotypes as extremes. Here, we focus on the effect of chemokines on macrophage differentiation and polarization in physiological and pathological conditions. In particular, we discuss chemokine-induced macrophage polarization in inflammatory diseases, including obesity, cancer, and atherosclerosis. [ABSTRACT FROM AUTHOR]

Background: Pulmonary embolism (PE) is a leading cause of cardiovascular mortality worldwide. Rapid and accurate diagnosis and risk stratification are crucial for timely treatment options, especially in high-risk PE., Objectives: The study aims to profile the comprehensive changes of plasma proteomes in PE patients and identify the potential biomarkers for both diagnosis and risk stratification., Patients/methods: Based on the data-independent acquisition mass spectrometry and antibody array proteomic technology, we screened the plasma samples (13 and 32 proteomes, respectively) in two independent studies consisting of high-risk PE patients, non-high-risk PE patients, and healthy controls. Some significantly differentially expressed proteins were quantified by ELISA in a new study group with 50 PE patients and 26 healthy controls., Results: We identified 207 and 70 differentially expressed proteins in PE and high-risk PE. These proteins were involved in multiple thrombosis-associated biological processes including blood coagulation, inflammation, injury, repair, and chemokine-mediated cellular response. It was verified that five proteins including SAA1, S100A8, TNC, GSN, and HRG had significant change in PE and/or in high-risk PE. The receiver operating characteristic curve analysis based on binary logistic regression showed that the area under the curve (AUC) of SAA1, S100A8, and TNC in PE diagnosis were 0.882, 0.788, and 0.795, and AUC of S100A8 and TNC in high-risk PE diagnosis were 0.773 and 0.720., Conclusion: As predictors of inflammation or injury repair, SAA1, S100A8, and TNC are potential plasma biomarkers for the diagnosis and risk stratification of PE., (© 2021 International Society on Thrombosis and Haemostasis.)

Upon inflammation, circulating monocytes leave the bloodstream and migrate into the tissues, where they differentiate after exposure to various growth factors, cytokines or infectious agents. The best defined macrophage polarization types are M1 and M2. However, the platelet-derived CXC chemokine CXCL4 induces the polarization of macrophages into a unique phenotype. In this study, we compared the effect of CXCL4 and its variant CXCL4L1 on the differentiation of monocytes into macrophages and into immature monocyte-derived dendritic cells (iMDDC). Differently to M-CSF and CXCL4, CXCL4L1 is not a survival factor for monocytes. Moreover, the expression of the chemokine receptors CCR2, CCR5 and CXCR3 was significantly higher on CXCL4L1-treated monocytes compared to M-CSF- and CXCL4-stimulated monocytes. IL-1 receptor antagonist (IL-1RN) expression was upregulated by CXCL4 and downregulated by CXCL4L1, respectively, whereas both chemokines reduced the expression of the mannose receptor (MRC). Furthermore, through activation of CXCR3, CXCL4L1-stimulated monocytes released significantly higher amounts of CCL2 and CXCL8 compared to CXCL4-treated monocytes, indicating more pronounced inflammatory traits for CXCL4L1. In contrast, in CXCL4L1-treated monocytes, the production of CCL22 was lower. Compared to iMDDC generated in the presence of CXCL4L1, CXCL4-treated iMDDC showed an enhanced phagocytic capacity and downregulation of expression of certain surface markers (e.g. CD1a) and specific enzymes (e.g. MMP-9 and MMP-12). CXCL4 and CXCL4L1 did not affect the chemokine receptor expression on iMDDC and cytokine production (CCL2, CCL18, CCL22, CXCL8, IL-10) by CXCL4- or CXCL4L1-differentiated iMDDC was similar. We can conclude that both CXCL4 and CXCL4L1 exert a direct effect on monocytes and iMDDC. However, the resulting phenotypes are different, which suggests a unique role for the two CXCL4 variants in physiology and/or pathology. [ABSTRACT FROM AUTHOR]

Background: CXCL4 is a platelet chemokine released at micromolar concentrations upon platelet activation. CXCL4 has been shown to promote atherogenesis by various mechanisms. However, data on CXCL4 plasma levels in patients with coronary artery disease are largely inconclusive. Computed coronary artery angiography (CCTA) represents an excellent tool to quantify and characterize coronary atherosclerotic plaques. We hypothesized that increased CXCL4 plasma levels may be associated with features of plaque instability resulting in adverse cardiovascular events. Specifically, we sought to determine whether CXCL4 levels are correlated with specific features of coronary artery disease including (1) plaque volume, (2) calcium score, (3) degree of stenosis, or (4) vascular remodeling. Methods and Results: CXCL4 plasma levels were measured by ELISA in 217 patients undergoing CCTA for suspected CAD (mean age 64.2 ± 9.4 years, 107 (49.3%) male). Mean CXCL4 plasma levels were 12.5 ± 4.6 ng/mL. There was no significant correlation between CXCL4 levels and any clinical or demographic parameters including cardiovascular risk factors. CXCL4 plasma levels did not differ between patient with or without coronary artery disease (CAD: 12.5 ± 4.5 ng/ml, no CAD: 12.5 ± 4.8 ng/ml). Neither univariate nor multivariate analysis showed an association between CXCL4 levels and plaque volume, total calcium score, degree of stenosis, or vascular remodeling. Subgroup analysis of patients with CAD as confirmed by CCTA did not show any association of CXCL4 levels with the extent of CAD. Conclusions: While CXCL4 may be present and active within the arterial wall, local increase of CXCL4 may not translate into systemically elevated CXCL4 levels. Further studies will have to test whether CXCL4 may still represent a suitable therapeutic target in human atherosclerosis. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the most life-threatening pathology worldwide. Its major clinical complications, stroke, myocardial infarction, and heart failure, are on the rise in many regions of the world-despite considerable progress in understanding cause, progression, and consequences of atherosclerosis. Originally perceived as a lipid-storage disease of the arterial wall (Die cellularpathologie in ihrer begründung auf physiologische und pathologische gewebelehre. August Hirschwald Verlag Berlin, []), atherosclerosis was recognized as a chronic inflammatory disease in 1986 (New Engl J Med 314:488-500, ). The presence of lymphocytes in atherosclerotic lesions suggested autoimmune processes in the vessel wall (Clin Exp Immunol 64:261-268, ). Since the advent of suitable mouse models of atherosclerosis (Science 258:468-471, ; Cell 71:343-353, ; J Clin Invest 92:883-893, ) and the development of flow cytometry to define the cellular infiltrate in atherosclerotic lesions (J Exp Med 203:1273-1282, ), the origin, lineage, phenotype, and function of distinct inflammatory cells that trigger or inhibit the inflammatory response in the atherosclerotic plaque have been studied. Multiphoton microscopy recently enabled direct visualization of antigen-specific interactions between T cells and antigen-presenting cells in the vessel wall (J Clin Invest 122:3114-3126, ). Vascular immunology is now emerging as a new field, providing evidence for protective as well as damaging autoimmune responses (Int Immunol 25:615-622, ). Manipulating inflammation and autoimmunity both hold promise for new therapeutic strategies in cardiovascular disease. Ongoing work (J Clin Invest 123:27-36, ; Front Immunol ; Semin Immunol 31:95-101, ) suggests that it may be possible to develop antigen-specific immunomodulatory prevention and therapy-a vaccine against atherosclerosis. [ABSTRACT FROM AUTHOR]

Macrophages display significant phenotypic heterogeneity. Two growth factors, macrophage colony-stimulating factor and chemokine (C-X-C motif) ligand 4, drive terminal differentiation of monocytes to M0 and M4 macrophages respectively. Compared to M0 macrophages, M4 cells have a unique transcriptome, with expression of surface markers such as S100A8, mannose receptor CD206 and matrix metalloproteinase 7. M4 macrophages did not express CD163, a scavenger receptor for haemoglobin/haptoglobin complex. Depending on the stimuli, M0 macrophages could polarize towards the proinflammatory M1 subset by treatment with lipopolysaccharide or interferon-γ. These macrophages produce a range of proinflammatory cytokines, nitric oxide, reactive oxygen species and exhibit high chemotactic and phagocytic activity. The alternative M2 type could be induced from M0 macrophage by stimulation with interleukin ( IL)-4. M2 macrophages express high levels of CD206 and produce anti-inflammatory cytokines IL-10 and transforming growth factor-β. M1, M2 and M4 macrophages could be found in atherosclerotic plaques. In the plaque, macrophages are subjected to the intensive influence not only by cytokines and chemokines but also with bioactive lipids such as cholesterol and oxidized phospholipids. Oxidized phospholipids induce a distinct Mox phenotype in murine macrophages that express a unique panel of antioxidant enzymes under control of the redox-regulated transcription factor Klf2, resistant to lipid accumulation. In unstable human lesions, atheroprotective M(Hb) and HA-mac macrophage subsets could be found. These two subsets are induced by the haemoglobin/haptoglobin complex, highly express haeme oxygenase 1 and CD163, and are implicated in clearance of haemoglobin and erythrocyte remnants. In atherogenesis, the macrophage phenotype is plastic and could therefore be switched to proinflammatory ( i.e. proatherogenic) and anti-inflammatory ( i.e. atheroprotective). The aim of this review was to characterize changes in macrophage transcriptome in atherosclerosis and discuss key markers that characterize different phenotypes of macrophages present in atherosclerotic lesions. [ABSTRACT FROM AUTHOR]

Background: Galectin-3 binding protein (Gal3BP), sCD163, galectin-3, and depression have been linked to cardiovascular disease and mortality. In patients with type 1 diabetes, female sex has also been linked to cardiovascular disease and mortality. The aim was to explore whether female sex, sCD163, galectin-3, and depression were associated with Gal3BP in patients with type 1 diabetes. We adjusted for metabolic variables, creatinine, smoking, physical inactivity, and cardiovascular disease. Methods: Cross-sectional design. Patients with type 1 diabetes (n = 285, women 44%, age18–59 years, diabetes duration 1–55 years) were consecutively recruited from one diabetes outpatient clinic. Blood samples, anthropometrics, and blood pressure were collected, supplemented with data from electronic medical records. High Gal3BP was defined as ≥3.3 mg/l (≥80th percentile). Depression was assessed by a self-report instrument. Linear and logistic regression models were elaborated for the associations and calibrated and validated for goodness of fit with the data variables. Results: Median (q1, q3) Gal3BP was 2.3 (1.8, 3.1) mg/l. The prevalence of high Gal3BP for women was 30% and 14% for men (p = 0.001). Female sex (adjusted odds ratio (AOR) 3.0), sCD163 (per μg/l) (AOR 6.6), and total cholesterol (per mmol/l) (AOR 1.6) were positively associated with high Gal3BP, and HDL-cholesterol (per mmol/l) (AOR 0.2) was negatively associated with high Gal3BP. Conclusions: High Gal3BP levels were associated with female sex, increasing sCD163 and total cholesterol levels, and decreasing HDL-cholesterol levels in patients with type 1 diabetes. The prevalence of high Gal3BP was more than twice as high in the women as in the men. [ABSTRACT FROM AUTHOR]

Background: Rupture-prone atherosclerotic plaques are characterized by heavy macrophage infiltration, and the presence of certain macrophage subsets might be a sign for plaque vulnerability. The mannose receptor (MR, CD206) is over-expressed in several types of alternatively activated macrophages. In this study, our objective was to evaluate the feasibility of a Gallium-68 (68Ga)-labelled anti-MR nanobody (68Ga-anti-MMR Nb) for the visualization of MR-positive (MR+) macrophages in atherosclerotic plaques of apolipoprotein E-knockout (ApoE-KO) mice.Results: NOTA-anti-MMR Nb was labelled with 68Ga with radiochemical purity > 95%. In vitro cell-binding studies demonstrated selective and specific binding of the tracer to M2a macrophages. For in vivo atherosclerotic plaque imaging studies, 68Ga-NOTA-anti-MMR Nb was injected into ApoE-KO and control mice intravenously (i.v.) and scanned 1 h post-injection for 30 min using a dedicated animal PET/CT. Focal signals could be detected in aortic tissue of ApoE-KO mice, whereas no signal was detected in the aortas of control mice. 68Ga-NOTA-anti-MMR Nb uptake was detected in atherosclerotic plaques on autoradiographs and correlated well with Sudan-IV-positive areas. The calculated ratio of plaque-to-normal aortic tissue autoradiographic signal intensity was 7.7 ± 2.6 in aortas excised from ApoE-KO mice. Immunofluorescence analysis of aorta cross-sections confirmed predominant MR expression in macrophages located in the fibrous cap layer and shoulder region of the plaques.Conclusions: 68Ga-NOTA-anti-MMR Nb allows non-invasive PET/CT imaging of MR expression in atherosclerotic lesions in a murine model and may represent a promising tool for clinical imaging and evaluation of plaque (in)stability. [ABSTRACT FROM AUTHOR]

Harvesting cultivated macrophages for tissue engineering purposes by enzymatic digestion of cell adhesion molecules can potentially result in unintended activation, altered function, or behavior of these cells. Thermo-responsive polymer is a promising tool that allows for gentle macrophage detachment without artificial activation prior to subculture within engineered tissue constructs. We therefore characterized different species of thermo-responsive polymers for their suitability as cell substrate and to mediate gentle macrophage detachment by temperature shift. Primary human monocyte- and THP-1-derived macrophages were cultured on thermo-responsive polymers and characterized for phagocytosis and cytokine secretion in response to lipopolysaccharide stimulation. We found that both cell types differentially respond in dependence of culture and stimulation on thermo-responsive polymers. In contrast to THP-1 macrophages, primary monocyte–derived macrophages showed no signs of impaired viability, artificial activation, or altered functionality due to culture on thermo-responsive polymers compared to conventional cell culture. Our study demonstrates that along with commercially available UpCell carriers, two other thermo-responsive polymers based on poly(vinyl methyl ether) blends are attractive candidates for differentiation and gentle detachment of primary monocyte–derived macrophages. In summary, we observed similar functionality and viability of primary monocyte–derived macrophages cultured on thermo-responsive polymers compared to standard cell culture surfaces. While this first generation of custom-made thermo-responsive polymers does not yet outperform standard culture approaches, our results are very promising and provide the basis for exploiting the unique advantages offered by custom-made thermo-responsive polymers to further improve macrophage culture and recovery in the future, including the covalent binding of signaling molecules and the reduction of centrifugation and washing steps. Optimizing these and other benefits of thermo-responsive polymers could greatly improve the culture of macrophages for tissue engineering applications. [ABSTRACT FROM AUTHOR]