Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases.
Obama Takashi,Itabe Hiroyuki
International journal of molecular sciences
Neutrophil extracellular traps (NETs) significantly contribute to various pathophysiological conditions, including cardiovascular diseases. NET formation in the vasculature exhibits inflammatory and thrombogenic activities on the endothelium. NETs are induced by various stimulants such as exogenous damage-associated molecular patterns (DAMPs). Oxidatively modified low-density lipoprotein (oxLDL) has been physiologically defined as a subpopulation of LDL that comprises various oxidative modifications in the protein components and oxidized lipids, which could act as DAMPs. oxLDL has been recognized as a crucial initiator and accelerator of atherosclerosis through foam cell formation by macrophages; however, recent studies have demonstrated that oxLDL stimulates neutrophils to induce NET formation and enhance NET-mediated inflammatory responses in vascular endothelial cells, thereby suggesting that oxLDL may be involved in cardiovascular diseases through neutrophil activation. As NETs comprise myeloperoxidase and proteases, they have the potential to mediate oxidative modification of LDL. This review summarizes recent updates on the analysis of NETs, their implications for cardiovascular diseases, and prospects for a possible link between NET formation and oxidative modification of lipoproteins.
Macrophages and Their Contribution to the Development of Atherosclerosis.
Bobryshev Yuri V,Nikiforov Nikita G,Elizova Natalia V,Orekhov Alexander N
Results and problems in cell differentiation
Atherosclerosis can be regarded as chronic inflammatory disease driven by lipid accumulation in the arterial wall. Macrophages play a key role in the development of local inflammatory response and atherosclerotic lesion growth. Atherosclerotic plaque is a complex microenvironment, in which different subsets of macrophages coexist executing distinct, although in some cases overlapping functions. According to the classical simplified nomenclature, lesion macrophages can belong to pro-inflammatory or anti-inflammatory or alternatively activated types. While the former promote the inflammatory response and participate in lipid accumulation, the latter are responsible for the inflammation resolution and plaque stabilisation. Atherosclerotic lesion dynamics depends therefore on the balance between these macrophages populations. The diverse functions of macrophages make them an attractive therapeutic target for the development of novel anti-atherosclerotic treatments. In this chapter, we discuss different types of macrophages and their roles in atherosclerotic lesion dynamics and describe the results of several experiments studying macrophage polarisation in atherosclerosis.
Monocyte fate in atherosclerosis.
Hilgendorf Ingo,Swirski Filip K,Robbins Clinton S
Arteriosclerosis, thrombosis, and vascular biology
Monocytes and their descendant macrophages are essential to the development and exacerbation of atherosclerosis, a lipid-driven inflammatory disease. Lipid-laden macrophages, known as foam cells, reside in early lesions and advanced atheromata. Our understanding of how monocytes accumulate in the growing lesion, differentiate, ingest lipids, and contribute to disease has advanced substantially over the last several years. These cells' remarkable phenotypic and functional complexity is a therapeutic opportunity: in the future, treatment and prevention of cardiovascular disease and its complications may involve specific targeting of atherogenic monocytes/macrophages and their products.
Inflammation-induced foam cell formation in chronic inflammatory disease.
Angelovich Thomas A,Hearps Anna C,Jaworowski Anthony
Immunology and cell biology
Atherosclerosis is the leading cause of cardiovascular disease and is both a metabolic and inflammatory disease. Two models describe early events initiating atherosclerotic plaque formation, whereby foam cells form in response to hyperlipidaemia or inflammation-associated stimuli. Although these models are inextricably linked and not mutually exclusive, identifying the unique contribution of each in different disease settings remains an important question. Circulating monocytes are key mediators of atherogenesis in both models as precursors to lipid-laden foam cells formed in response to either excess lipid deposition in arteries, signalling via pattern-associated molecular patterns or a combination of the two. In this review, we assess the role of monocytes in each model and discuss how key steps in atherogenesis may be targeted to enhance clinical outcomes in patients with chronic inflammatory disease.
Effects of dyslipidaemia on monocyte production and function in cardiovascular disease.
Rahman Mohammed Shamim,Murphy Andrew J,Woollard Kevin J
Nature reviews. Cardiology
Monocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. Monocytes and macrophages are involved in cardiovascular disease progression, and are associated with the development of unstable atherosclerotic plaques. Hyperlipidaemia can accelerate cardiovascular disease progression. However, monocyte responses to hyperlipidaemia are poorly understood. In the past decade, accumulating data describe the relationship between the dynamic blood lipid environment and the heterogeneous circulating monocyte pool, which might have profound consequences for cardiovascular disease. In this Review, we explore the updated view of monocytes in cardiovascular disease and their relationship with macrophages in promoting the homeostatic and inflammatory responses related to atherosclerosis. We describe the different definitions of dyslipidaemia, highlight current theories on the ontogeny of monocyte heterogeneity, discuss how dyslipidaemia might alter monocyte production, and explore the mechanistic interface linking dyslipidaemia with monocyte effector functions, such as migration and the inflammatory response. Finally, we discuss the role of dietary and endogenous lipid species in mediating dyslipidaemic responses, and the role of these lipids in promoting the risk of cardiovascular disease through modulation of monocyte behaviour.
Monocytes in atherosclerosis: subsets and functions.
Woollard Kevin J,Geissmann Frederic
Nature reviews. Cardiology
Chronic inflammation drives atherosclerosis, the leading cause of cardiovascular disease. Over the past two decades, data have emerged showing that immune cells are involved in the pathogenesis of atherosclerotic plaques. The accumulation and continued recruitment of leukocytes are associated with the development of 'vulnerable' plaques. These plaques are prone to rupture, leading to thrombosis, myocardial infarction or stroke, all of which are frequent causes of death. Plaque macrophages account for the majority of leukocytes in plaques, and are believed to differentiate from monocytes recruited from circulating blood. However, monocytes represent a heterogenous circulating population of cells. Experiments are needed to address whether monocyte recruitment to plaques and effector functions, such as the formation of foam cells, the production of nitric oxide and reactive oxygen species, and proteolysis are critical for the development and rupture of plaques, and thus for the pathophysiology of atherosclerosis, as well as elucidate the precise mechanisms involved.
The fate of monocytes in atherosclerosis.
Randolph G J
Journal of thrombosis and haemostasis : JTH
Monocytes are the primary inflammatory cell type that infiltrates early atherosclerotic plaques. Their recruitment into plaques drives disease progression. Disease interventions that target monocytes could act at several points: alteration in the phenotype of circulating monocyte subpopulations; reduced recruitment of monocytes into plaques; alterations in the survival of monocyte-derived cells in atherosclerosis; and promotion of migratory egress from plaques to bring about resolution of the plaque inflammatory response. All of these points of intervention will be briefly discussed in this article.
The role of monocytes in atherosclerotic coronary artery disease.
Pamukcu Burak,Lip Gregory Y H,Devitt Andrew,Griffiths Helen,Shantsila Eduard
Annals of medicine
Inflammation plays a key role in the pathogenesis of atherosclerosis. The more we discover about the molecular pathways involved in atherosclerosis, the more we perceive the importance of monocytes in this process. Circulating monocytes are components of innate immunity, and many pro-inflammatory cytokines and adhesion molecules facilitate their adhesion and migration to the vascular endothelial wall. In addition to the accumulation of lipids and formation of atherogenic 'foam' cells, monocytes may promote atherosclerotic plaque growth by production of inflammatory cytokines, matrix metalloproteinases, and reactive oxidative species. However, the contribution of monocytes to atherogenesis is not only limited to tissue destruction. Monocyte subsets are also involved in intraplaque angiogenesis and tissue reparative processes. The aim of this overview is to discuss the mechanisms of monocyte activation, the pivotal role and importance of activated monocytes in atherosclerotic coronary artery disease, their implication in the development of acute coronary events, and their potential in cardiovascular reparative processes such angiogenesis.
Nature versus Number: Monocytes in Cardiovascular Disease.
Williams Helen,Mack Corinne D,Li Stephen C H,Fletcher John P,Medbury Heather J
International journal of molecular sciences
Monocytes play a key role in cardiovascular disease (CVD) as their influx into the vessel wall is necessary for the development of an atherosclerotic plaque. Monocytes are, however, heterogeneous differentiating from classical monocytes through the intermediate subset to the nonclassical subset. While it is recognized that the percentage of intermediate and nonclassical monocytes are higher in individuals with CVD, accompanying changes in inflammatory markers suggest a functional impact on disease development that goes beyond the increased proportion of these 'inflammatory' monocyte subsets. Furthermore, emerging evidence indicates that changes in monocyte proportion and function arise in dyslipidemia, with lipid lowering medication having some effect on reversing these changes. This review explores the nature and number of monocyte subsets in CVD addressing what they are, when they arise, the effect of lipid lowering treatment, and the possible implications for plaque development. Understanding these associations will deepen our understanding of the clinical significance of monocytes in CVD.
Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation.
Van Avondt Kristof,Maegdefessel Lars,Soehnlein Oliver
Thrombosis and haemostasis
Neutrophils and neutrophil extracellular traps (NETs) have a robust relationship with atherothrombotic disease risk, which led to the idea that interfering with the release of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute coronary events and the pro-thrombotic state cause markedly elevated levels of circulating deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency and showed a significant benefit for atherothrombotic disease in experimental mouse models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms underlying NET release and atherogenic inflammation have come from transgenic mouse studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic disease has been shown and linked to profound pro-inflammatory and pro-thrombotic effects, complement activation and endothelial dysfunction. Recent studies have shown that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects against atherosclerosis burden, propagation of its thrombotic complications and notably macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol accumulation have emerged as important factors driving NET release, likely involving mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for cardiovascular diseases.
Update on selective treatments targeting neutrophilic inflammation in atherogenesis and atherothrombosis.
Gomes Quinderé Ana Luíza,Benevides Norma Maria Barros,Carbone Federico,Mach François,Vuilleumier Nicolas,Montecucco Fabrizio
Thrombosis and haemostasis
Atherosclerosis is the most common pathological process underlying cardiovascular diseases. Current therapies are largely focused on alleviating hyperlipidaemia and preventing thrombotic complications, but do not completely eliminate risk of suffering recurrent acute ischaemic events. Specifically targeting the inflammatory processes may help to reduce this residual risk of major adverse cardiovascular events in atherosclerotic patients. The involvement of neutrophils in the pathophysiology of atherosclerosis is an emerging field, where evidence for their causal contribution during various stages of atherosclerosis is accumulating. Therefore, the identification of neutrophils as a potential therapeutic target may offer new therapeutic perspective to reduce the current atherosclerotic burden. This narrative review highlights the expanding role of neutrophils in atherogenesis and discusses on the potential treatment targeting neutrophil-related inflammation and associated atherosclerotic plaque vulnerability.
Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease.
Klopf Johannes,Brostjan Christine,Eilenberg Wolf,Neumayer Christoph
International journal of molecular sciences
Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient's immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.
Multiple roles for neutrophils in atherosclerosis.
Because of their rare detection in atherosclerotic lesions, the involvement of neutrophils in the pathophysiology of atherosclerosis has been largely denied. However, over the past couple of years, studies have provided convincing evidence for the presence of neutrophils in atherosclerotic plaques and further revealed the causal contribution of neutrophils during various stages of atherosclerosis. This review describes mechanisms underlying hyperlipidemia-mediated neutrophilia and how neutrophils may enter atherosclerotic lesions. It also highlights possible mechanisms of neutrophil-driven atherogenesis and plaque destabilization. Knowledge of the contribution of neutrophils to atherosclerosis will allow for exploration of new avenues in the treatment of atherogenesis and atherothrombosis.
Neutrophils in atherosclerosis. A brief overview.
Hartwig H,Silvestre Roig C,Daemen M,Lutgens E,Soehnlein O
Atherosclerosis is a chronic inflammation of the arterial wall and the continuous infiltration of leukocytes into the plaque enhances the progression of the lesion. Because of the scarce detection of neutrophils in atherosclerotic plaques compared to other immune cells, their contribution was largely neglected. However, in the last years studies have accumulated pointing towards the contribution of neutrophils to atherogenesis. In addition, studies are emerging implying a role for neutrophils in advanced atherosclerosis and/or plaque destabilization. Thus, this brief review delivers an overview of the role of neutrophils during early and late stage atherosclerosis.
Polymorphonuclear neutrophils and instability of the atherosclerotic plaque: a causative role?
Della Bona Roberta,Cardillo Maria Teresa,Leo Milena,Biasillo Gina,Gustapane Massimo,Trotta Francesco,Biasucci Luigi M
Inflammation research : official journal of the European Histamine Research Society ... [et al.]
OBJECTIVE:The aim of this review is to examine the role of polymorphonuclear neutrophils (PMNs) in the evolution of atherosclerosis. INTRODUCTION:While the role of PMNs in the evolution of atherosclerosic process has failed until recently to attract much attention, a body of research carried out over the last decade has disclosed the unexpectedly complex behavior of these cells, unraveling an unexpected key role for PMNs in the onset and progression of atheroma. METHODS:A PubMed database search was performed for studies providing evidences on the role of PMNs in the development and progression of atherosclerotic lesion. RESULTS AND CONCLUSIONS:Activated PMNs were shown to produce and release reactive oxygen species, inflammatory leukotrienes and proteolytic lysosomal enzymes, directly inducing vascular damage. Activated PMNs also secrete myeloperoxidase, involved in lipoprotein oxidation. PMNs have a finite lifespan and typically die through apoptosis, which thus represents a counter-regulatory mechanism limiting the toxic potential of these short-lived, terminally differentiated cells. Dysregulation of this process probably contributes to the pathogenesis and progression of several inflammatory diseases. Moreover, high circulating levels of PMN-platelet aggregates have been reported in patients with clinical atherosclerosis, and recent studies suggest that these aggregates may play a role in vascular response to injury. It has been suggested that this heterotypic interaction between platelets and leukocytes might represent a link between hemostasis/thrombosis and the inflammatory response.
Update on the role of neutrophils in atherosclerotic plaque vulnerability.
Carbone Federico,Mach Francois,Montecucco Fabrizio
Current drug targets
Atherosclerosis is the main pathophysiological process underlying acute cardiovascular diseases. Life-threatening conditions, such as myocardial infarction and ischemic stroke, are provoked by the sudden rupture of vulnerable atherosclerotic plaques, characterized by thin, highly inflamed and collagen-poor fibrous cap. Whereas both innate and adaptive inflammation progressively emerged as driving force of this processes, less is known about the involvement of neutrophils (PMNs). Advances in laboratory techniques during the last two decades disclosed that PMNs play a crucial role in promoting plaque vulnerability by the release of different enzymes, such as gelatinases (matrix metalloproteinases) collagenases, elastase and myeloperoxidase. Accordingly, circulating levels of PMNs and their products have been investigated as potential markers of plaque instability in both primary and secondary prevention on cardiovascular diseases. In addition, the development of different classes of drugs targeting PMNs activation is emerging as an interesting field of research. This narrative review will provide an update on the role of PMNs in promoting plaque vulnerability also discussing the potential effects of therapeutic strategies targeting PMN on plaque vulnerability.
Inflammation in atherosclerosis: transition from theory to practice.
Libby Peter,Okamoto Yoshihisa,Rocha Viviane Z,Folco Eduardo
Circulation journal : official journal of the Japanese Circulation Society
Inflammation drives the formation, progression, and rupture of atherosclerotic plaques. Experimental studies have demonstrated that an inflammatory subset of monocytes/macrophages preferentially accumulate in atherosclerotic plaque and produce proinflammatory cytokines. T lymphocytes can contribute to inflammatory processes that promote thrombosis by stimulating production of collagen-degrading proteinases and the potent procoagulant tissue factor. Recent data link obesity, inflammation, and modifiers of atherosclerotic events, a nexus of growing clinical concern given the worldwide increase in the prevalence of obesity. Modulators of inflammation derived from visceral adipose tissue evoke production of acute phase reactants in the liver, implicated in thrombogenesis and clot stability. Additionally, C-reactive protein levels rise with increasing levels of visceral adipose tissue. Adipose tissue in obese mice contains increased numbers of macrophages and T lymphocytes, increased T lymphocyte activation, and increased interferon-gamma (IFN-gamma) expression. IFN-gamma deficiency in mice reduces production of inflammatory cytokines and inflammatory cell accumulation in adipose tissue. Another series of in vitro and in vivo mouse experiments affirmed that adiponectin, an adipocytokine, the plasma levels of which drop with obesity, acts as an endogenous antiinflammatory modulator of both innate and adaptive immunity in atherogenesis. Thus, accumulating experimental evidence supports a key role for inflammation as a link between risk factors for atherosclerosis and the biology that underlies the complications of this disease. The recent JUPITER trial supports the clinical utility of an assessment of inflammatory status in guiding intervention to limit cardiovascular events. Inflammation is thus moving from a theoretical concept to a tool that provides practical clinical utility in risk assessment and targeting of therapy.
Correlation between immunological-inflammatory markers and endothelial disfunction in the early stage of coronary heart disease.
Persic Viktor,Bastiancic Ana Lanca,Rosovic Ivan,Raljevic Damir,Samsa Dijana Travica,Bastiancic Luka,Miskulin Rajko,Boban Marko,Laskarin Gordana
Classical risk factors for endothelial dysfunction (ED), such as age, gender, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, and smoking history are utilised for the Framingham score and Systemic Coronary Risk Estimation (SCORE) for evaluation of the 10-year cardiovascular risk in routine practice. Nonetheless, pro-inflammatory mediators are deeply involved in the initiation and the progression of ED and coronary artery disease (CAD), and act additionally or independently of metabolic factors before clinical manifestations of the disease appear. C-reactive protein, a marker of intimal thickening of the myeloid-related protein 8/14 heterodimer, monocyte chemotactic protein 1, interleukin-15, the cytotoxic mediator, granulysin, and the matrix metalloproteinase 9 could be valuable, single, fast, and non-invasive laboratory tools for ED deterioration degree assessment. We propose to investigate the impact of pro-inflammatory biomarkers on ED, measured by previously established clinical methods in patients with yet undiagnosed CAD and at medium risk for an acute coronary event. It could be useful to measure and correlate the concentration of particular inflammatory markers in peripheral blood samples and the results of the Framingham and SCORE charts, multi-slice computed tomography coronary angiography, echocardiography, brachial artery flow-mediated dilatation, carotid-femoral pulse wave velocity, ankle-brachial index, carotid wall thickening, myocardial perfusion scintigraphy, and particularly, cardiac magnetic resonance imaging. The goal would be that the degree of correlation between particular inflammatory markers and the results of some methods for the assessment of ED or cardiac ischaemic imaging could be emphasised and pro-inflammatory markers positioned in the pathogenetic algorithm of CAD.
Novel findings in neutrophil biology and their impact on cardiovascular disease.
Bonaventura Aldo,Montecucco Fabrizio,Dallegri Franco,Carbone Federico,Lüscher Thomas F,Camici Giovanni G,Liberale Luca
Neutrophils are the most abundant circulating leucocytes in healthy humans. These cells are central players during acute inflammatory responses, although a growing body of evidence supports a crucial role in chronic inflammation and chemokines and cytokines related to it as well. Thus, both humoral and cellular components are involved in the development of plaque formation and atherosclerosis. Accordingly, CANTOS trial using an interleukin-1 beta antibody confirmed that inflammatory cytokines contribute to the occurrence of myocardial infarction and cardiac death independent of changes in lipids. Recent data revealed that neutrophils are a heterogeneous population with different subsets and functional characteristics (i.e. CD177+ cells, OLFM4+ neutrophils, proangiogenic neutrophils, neutrophils undergoing reverse migration, and aged neutrophils). Importantly, neutrophils are able to synthesize de novo proteins. Neutrophil extracellular trap generation and NETosis have been considered as very important weapons in sterile inflammation. Neutrophil-derived microvesicles represent another mechanism by which neutrophils amplify inflammatory processes, being found at high levels both at the site of injury and in the bloodstream. Finally, neutrophil aging can influence their functions also in relation with host age. These recent acquisitions in the field of neutrophil biology might pave the way for new therapeutic targets to prevent or even treat patients experiencing cardiovascular (CV) diseases. Here, we discuss novel findings in neutrophil biology, their impact on CV and cerebrovascular diseases, and the potential implementation of these notions into daily clinical practice.
Oxidative Stress and Inflammation, Key Targets of Atherosclerotic Plaque Progression and Vulnerability: Potential Impact of Physical Activity.
Mury Pauline,Chirico Erica N,Mura Mathilde,Millon Antoine,Canet-Soulas Emmanuelle,Pialoux Vincent
Sports medicine (Auckland, N.Z.)
Atherosclerosis, a complex cardiovascular disease, is a leading cause of mortality and morbidity worldwide. Oxidative stress and inflammation are both involved in the development of atherosclerotic plaque as they increase the biological processes associated with this pathology, such as endothelial dysfunction and macrophage recruitment and adhesion. Atherosclerotic plaque rupture leading to major ischemic events is the result of vulnerable plaque progression, which is a result of the detrimental effect of oxidative stress and inflammation on risk factors for atherosclerotic plaque rupture, such as intraplaque hemorrhage, neovascularization, and fibrous cap thickness. Thus, both are key targets for primary and secondary interventions. It is well recognized that chronic physical activity attenuates oxidative stress in healthy subjects via the improvement of antioxidant enzyme capacities and inflammation via the enhancement of anti-inflammatory molecules. Moreover, it was recently shown that chronic physical activity could decrease oxidative stress and inflammation in atherosclerotic patients. The aim of this review is to summarize the role of oxidative stress and inflammation in atherosclerosis and the results of therapeutic interventions targeting them in both preclinical and clinical studies. The effects of chronic physical activity on these two key processes are then reviewed in vulnerable atherosclerotic plaques in both coronary and carotid arteries.
The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques.
Rai Vikrant,Agrawal Devendra K
Canadian journal of physiology and pharmacology
Atherosclerosis is a chronic inflammatory disease resulting in the formation of the atherosclerotic plaque. Plaque formation starts with the inflammation in fatty streaks and progresses through atheroma, atheromatous plaque, and fibroatheroma leading to development of stable plaque. Hypercholesterolemia, dyslipidemia, and hyperglycemia are the risk factors for atherosclerosis. Inflammation, infection with viruses and bacteria, and dysregulation in the endothelial and vascular smooth muscle cells leads to advanced plaque formation. Death of the cells in the intima due to inflammation results in secretion of damage-associated molecular patterns (DAMPs) such as high mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), alarmins (S100A8, S100A9, S100A12, and oxidized low-density lipoproteins), and infection with pathogens leads to secretion of pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides, lipoteichoic acids, and peptidoglycans. DAMPs and PAMPs further activate the inflammatory surface receptors such as TREM-1 and toll-like receptors and downstream signaling kinases and transcription factors leading to increased secretion of pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1β, IL-6, and interferon-γ and matrix metalloproteinases (MMPs). These mediators and cytokines along with MMPs render the plaque vulnerable for rupture leading to ischemic events. In this review, we have discussed the role of DAMPs and PAMPs in association with inflammation-mediated plaque vulnerability.
Inflammasomes, neutrophil extracellular traps, and cholesterol.
Tall Alan R,Westerterp Marit
Journal of lipid research
Activation of macrophage inflammasomes leads to interleukin (IL)-1β and IL-18 secretion and promotes atherosclerosis and its complications in mice and humans. However, the specific role and underlying mechanisms of the inflammasome in atherogenesis are topics of active research. Several studies in hyperlipidemic mouse models found that the NOD-like receptor protein 3 (NLRP3) inflammasome contributes to atherosclerosis, but recent work suggests that a second hit, such as defective cholesterol efflux or accumulation of oxidized mitochondrial DNA, may be required for significant inflammasome activation. Cholesterol crystal uptake or formation in lysosomes may damage membranes and activate NLRP3 inflammasomes. Alternatively, plasma or ER membrane cholesterol accumulation may condition macrophages for inflammasome activation in the presence of danger-associated molecular patterns, such as oxidized LDL. Inflammasome activation in macrophages or neutrophils leads to gasdermin-D cleavage that induces membrane pore formation, releasing IL-1β and IL-18, and eventuating in pyroptosis or neutrophil extracellular trap formation (NETosis). In humans, inflammasome activation and NETosis may contribute to atherosclerotic plaque erosion and thrombosis, especially in patients with type 2 diabetes, chronic kidney disease, or clonal hematopoiesis. Suppression of the inflammasome by activation of cholesterol efflux or by direct inhibition of inflammasome components may benefit patients with CVD and underlying susceptibility to inflammasome activation.
Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease.
Prame Kumar Kathryn,Nicholls Alyce J,Wong Connie H Y
Cell and tissue research
Neutrophils are becoming recognized as highly versatile and sophisticated cells that display de novo synthetic capacity and potentially prolonged lifespan. Emerging concepts such as neutrophil heterogeneity and plasticity have revealed that, under pathological conditions, neutrophils may differentiate into discrete subsets defined by distinct phenotypic and functional characteristics. Indeed, these newly described neutrophil subsets will undoubtedly add to the already complex interactions between neutrophils and other immune cell types for an effective immune response. The interactions between neutrophils and monocytes/macrophages enable the host to efficiently defend against and eliminate foreign pathogens. However, it is also becoming increasingly clear that these interactions can be detrimental to the host if not tightly regulated. In this review, we will explore the functional cooperation of neutrophil and monocytes/macrophages in homeostasis, during acute inflammation and in various disease settings. We will discuss this in the context of cardiovascular disease in the form of atherosclerosis, an autoimmune disease mainly occurring in the kidneys, as well as the unique intestinal immune response of the gut that does not conform to the norms of the typical immune system.
Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions.
Raggi Paolo,Genest Jacques,Giles Jon T,Rayner Katey J,Dwivedi Girish,Beanlands Robert S,Gupta Milan
Rudolph Virchow (1821-1902) recognized inflammation in histological preparations of coronary arteries and proposed that inflammation plays a causal role in atherosclerosis. Despite this seminal observation, the main focus of research and drug development programs has been cholesterol alone, and inflammation received less attention over time. However, during the past several decades extensive observations supported the importance of inflammation in the development and destabilization of atherosclerosis. Studies in patients affected by rheumatological diseases suggested an interaction between chronic inflammation and atherosclerotic cardiovascular disease. Randomized clinical studies with lipid lowering agents suggested that part of the beneficial effect may have been related to reduction in inflammation. More recently, a few studies were designed to directly address the role of anti-inflammatory treatments in reducing risk of atherosclerotic heart disease beyond traditional risk factors. In this article, we review the pathophysiologic contribution of inflammation to atherosclerosis, biomarkers of inflammation and the evidence collected in observational studies regarding the role of chronic inflammation in the development of atherosclerotic heart disease. Finally, we discuss the most recent randomized clinical trials of anti-inflammatory agents directed at stemming atherosclerotic cardiovascular disease.
Neutrophil effector responses are suppressed by secretory phospholipase A2 modified HDL.
Curcic Sanja,Holzer Michael,Frei Robert,Pasterk Lisa,Schicho Rudolf,Heinemann Akos,Marsche Gunther
Biochimica et biophysica acta
Secretory phospholipase A2 (sPLA2) generates bioactive lysophospholipids implicated in acute and chronic inflammation, but the pathophysiologic role of sPLA2 is poorly understood. Given that high-density lipoprotein (HDL) is the major substrate for sPLA2 in plasma, we investigated the effects of sPLA2-mediated modification of HDL (sPLA2-HDL) on neutrophil function, an essential arm of the innate immune response and atherosclerosis. Treatment of neutrophils with sPLA2-HDL rapidly prevented agonist-induced neutrophil activation, including shape change, neutrophil extracellular trap formation, CD11b activation, adhesion under flow and migration of neutrophils. The cholesterol-mobilizing activity of sPLA2-HDL was markedly increased when compared to native HDL, promoting a significant reduction of cholesterol-rich signaling microdomains integral to cellular signaling pathways. Moreover, sPLA2-HDL effectively suppressed agonist-induced rise in intracellular Ca²⁺ levels. Native HDL showed no significant effects and removing lysophospholipids from sPLA2-HDL abolished all anti-inflammatory activities. Overall, our studies suggest that the increased cholesterol-mobilizing activity of sPLA2-HDL and suppression of rise in intracellular Ca²⁺ levels are likely mechanism that counteracts agonist-induced activation of neutrophils. These counterintuitive findings imply that neutrophil trafficking and effector responses are altered by sPLA2-HDL during inflammatory conditions.
Evaluation of complete blood count parameters in cardiovascular diseases: An early indicator of prognosis?
Haybar Habib,Pezeshki Seyed Mohammad Sadegh,Saki Najmaldin
Experimental and molecular pathology
BACKGROUND:Studies have been conducted to evaluate the correlation between complete blood count (CBC) indices and cardiovascular diseases (CVDs). Considering the dispersion of these studies as well as reports on prognostic value of CBC parameters in CVDs, we have summarized these findings as a review article for the first time. METHODS:Relevant English language literature was searched and retrieved from Google Scholar search engine and PubMed database (1996-2018). We used "Complete blood count", "Cardiovascular disease", "Red cell distribution width", and "Mean platelet volume" as keywords. RESULTS:Numerous studies indicated that red cell distribution width (RDW) is an independent prognostic biomarker in relation to CVD diseases. MPV is another considerable prognostic biomarker for CVDs. Elevations of inflammatory markers such as neutrophil to lymphocyte ratio (NLR) in CVD patients (especially in myocardial infarction and heart failure) can be considered as a factor of poor prognosis. CONCLUSIONS:RDW can be used as a valuable independent biomarker to investigate the prognosis of patients with heart failure (HF), atherosclerosis, myocardial infarction (MI), and other CVDs. Rapid and stable increase in MPV makes it a reliable prognostic/diagnostic parameter in CVDs such as MI and unstable angina. Among different inflammatory markers the evaluation of total white blood cell count, NLR, monocyte to high-density lipoprotein ratio (MHR) and platelet to lymphocyte ratio (PLR) may have a high value in predicting the prognosis of different CVDs including MI, HF and atherosclerosis in patients.
Inflammation: a trigger for acute coronary syndrome.
Sager Hendrik B,Nahrendorf Matthias
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...
Atherosclerosis is a chronic inflammatory disease of the vessel wall and a major cause of death worldwide. One of atherosclerosis' most dreadful complications are acute coronary syndromes that comprise ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, and unstable angina. We now understand that inflammation substantially contributes to the initiation, progression, and destabilization of atherosclerosis. In this review, we will focus on the role of inflammatory leukocytes, which are the cellular protagonists of vascular inflammation, in triggering disease progression and, ultimately, the destabilization that causes acute coronary syndromes.
Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis.
Rasheed Adil,Cummins Carolyn L
International journal of molecular sciences
Atherosclerosis is a chronic condition associated with cardiovascular disease. While largely identified by the accumulation of lipid-laden foam cells within the aorta later on in life, atherosclerosis develops over several stages and decades. During atherogenesis, various cell types of the aorta acquire a pro-inflammatory phenotype that initiates the cascade of signaling events facilitating the formation of these foam cells. The liver X receptors (LXRs) are nuclear receptors that upon activation induce the expression of transporters responsible for promoting cholesterol efflux. In addition to promoting cholesterol removal from the arterial wall, LXRs have potent anti-inflammatory actions via the transcriptional repression of key pro-inflammatory cytokines. These beneficial functions sparked an interest in the potential to target LXRs and the development of agonists as anti-atherogenic agents. These early studies focused on mediating the contributions of macrophages to the underlying pathogenesis. However, further evidence has since demonstrated that LXRs reduce atherosclerosis through their actions in multiple cell types apart from those monocytes/macrophages that infiltrate the lesion. LXRs and their target genes have profound effects on multiple other cells types of the hematopoietic system. Furthermore, LXRs can also mediate dysfunction within vascular cell types of the aorta including endothelial and smooth muscle cells. Taken together, these studies demonstrate the whole-body benefits of LXR activation with respect to anti-atherogenesis, and that LXRs remain a viable target for the treatment of atherosclerosis, with a reach which extends beyond plaque macrophages.
Critical roles of inflammation in atherosclerosis.
Journal of cardiology
There is accumulating evidence that vascular inflammation plays critical roles in pathophysiology of atherosclerosis. It is widely accepted that both innate and adaptive immune responses are important for initiation and progression of atherosclerosis, which mainly consist of monocytes, macrophages, neutrophils, T lymphocytes, and B lymphocytes. Moreover, inflammatory biomarkers such as high-sensitivity C-reactive protein and interleukin-6 are known to predict future cardiovascular events, as well as conventional low-density or high-density lipoprotein cholesterol. Thus, current understanding of the inflammatory mechanisms of atherosclerosis have led us to explore novel therapeutic approaches that reducing vascular inflammation itself could lower the rates of critical cardiovascular events. To address the inflammatory hypothesis of atherosclerosis, results of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial have been recently reported that anti-inflammatory therapy using canakinumab, a monoclonal antibody targeting interleukin-1β, significantly reduced recurrent cardiovascular events for secondary prevention of myocardial infarction at high inflammatory risk. In this review, we will first outline the mechanisms of atherosclerosis, especially focusing on their inflammatory aspects. Then we will introduce several critical inflammatory biomarkers that contribute to risk stratification of clinical cardiovascular events. Lastly, we will discuss potentiality and future perspectives of reducing inflammation as a novel therapeutic target for atherosclerotic cardiovascular diseases.
Follicular regulatory T cell in atherosclerosis.
Baptista Daniela,Mach François,Brandt Karim J
Journal of leukocyte biology
Atherosclerosis is a chronic inflammatory disease involving the infiltration of immune cells, such as monocytes/macrophages, neutrophils, T cells, and B cells, into the inner layer of vessel walls. T and B cell functions in the process of atherogenesis, as well as their mutual regulation, have been investigated but several aspects remain to be clarified. In the present review, we give a brief overview of the functions of follicular regulatory T cell (Tfr) on follicular T (Tfh) and B cell regulation related to atherosclerosis pathogenesis, including their influence on lymphangiogenesis and lipoprotein metabolism. We will also discuss their potential therapeutics properties in the resolution of established atherosclerotic lesions.
The Phenomenon of Neutrophil Extracellular Traps in Vascular Diseases.
Dąbrowska Dorota,Jabłońska Ewa,Garley Marzena,Sawicka-Powierza Jolanta,Nowak Karolina
Archivum immunologiae et therapiae experimentalis
Vascular diseases constitute a global health issue due to the increasing number of cases of patients with these diseases. The pathogenesis of the majority of these diseases, including atherosclerosis and thrombosis, is complex and not yet fully understood. One of the major causes for their occurrence can be immune disorders resulting in the development of a chronic inflammation within the vessels. In recent years, studies have placed emphasis on the role of neutrophils in the development of these diseases, i.e., the discovery of neutrophil extracellular traps (NETs) demonstrated that the structures released by the cells may contribute to the enhancement of inflammatory reactions and cell damage. This article summarizes current knowledge on the role of NETs during atherosclerosis, thrombosis and small-vessel vasculitis, especially in antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (AAV).
Platelet-neutrophil interactions as drivers of inflammatory and thrombotic disease.
Cell and tissue research
Neutrophils are well known for their role in infection and inflammatory disease and are first responders at sites of infection or injury. Platelets have an established role in hemostasis and thrombosis and are first responders at sites of vascular damage. However, neutrophils are increasingly recognized for their role in thrombosis, while the immunemodulatory properties of platelets are being increasingly studied. Platelets and neutrophils interact during infection, inflammation and thrombosis and modulate each other's functions. This review will discuss the consequences of platelet-neutrophil interactions in infection, thrombosis, atherosclerosis and tissue injury and repair.
The pathway of neutrophil extracellular traps towards atherosclerosis and thrombosis.
Moschonas Iraklis C,Tselepis Alexandros D
Neutrophil extracellular traps (NETs) are web-like extrusions of genetic material, which are released upon neutrophil activation. NETs consist of a chromatin substructure, onto which a vast array of proteins with various properties is dispersed. NETs production was initially described as an unrecognized defense mechanism of neutrophils, due to their ability to entrap and possibly eliminate a wide range of pathogens. Nevertheless, growing evidence suggests that NETs are implicated in a multitude of pathophysiological conditions, such as autoimmunity, cancer, diabetes mellitus and Alzheimer's disease. Importantly, NETs may also play a decisive role in atherosclerosis and thrombosis. In this context, it has been demonstrated that NETs are present in atherosclerotic lesions of both humans and animal models and are implicated in various mechanisms leading to atherogenesis. Among others, NETs induce oxidative stress and oxidize high-density lipoprotein particles, thus reducing their beneficial cholesterol efflux capacity. NETs also induce endothelial cell dysfunction and apoptosis and promote the generation of anti-double-stranded-DNA autoantibodies. NETs may also play a prothrombotic role, since they form a fibrin-like base for platelet adhesion, activation and aggregation. Furthermore, NETs promote the accumulation of prothrombotic molecules, like von Willebrand factor and fibrinogen, thus significantly contributing to thrombus formation. Notably, there is vast data linking NETs to arterial and venous thrombosis in animal models, as well as in humans. Future large-scale studies should incorporate NETs and their individual components as disease markers, as well as potential therapeutic targets, to reduce atherosclerosis and to prevent thrombosis.
Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis.
Döring Yvonne,Soehnlein Oliver,Weber Christian
Neutrophil extracellular traps expelled from suicidal neutrophils comprise a complex structure of nuclear chromatin and proteins of nuclear, granular, and cytosolic origin. These net-like structures have also been detected in atherosclerotic lesions and arterial thrombi in humans and mice. Functionally, neutrophil extracellular traps have been shown to induce activation of endothelial cells, antigen-presenting cells, and platelets, resulting in a proinflammatory immune response. Overall, this suggests that they are not only present in plaques and thrombi but also they may play a causative role in triggering atherosclerotic plaque formation and arterial thrombosis. This review will focus on current findings of the involvement of neutrophil extracellular traps in atherogenesis and atherothrombosis.
Mechanisms of erosion of atherosclerotic plaques.
Quillard Thibaut,Franck Grégory,Mawson Thomas,Folco Eduardo,Libby Peter
Current opinion in lipidology
PURPOSE OF REVIEW:The present review explores the mechanisms of superficial intimal erosion, a common cause of thrombotic complications of atherosclerosis. RECENT FINDINGS:Human coronary artery atheroma that give rise to thrombosis because of erosion differ diametrically from those associated with fibrous cap rupture. Eroded lesions characteristically contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps (NETs). Innate immune mechanisms such as engagement of Toll-like receptor 2 (TLR2) on cultured endothelial cells can impair their viability, attachment, and ability to recover a wound. Hyaluronan fragments may serve as endogenous TLR2 ligands. Mouse experiments demonstrate that flow disturbance in arteries with neointimas tailored to resemble features of human eroded plaques disturbs endothelial cell barrier function, impairs endothelial cell viability, recruits neutrophils, and provokes endothelial cells desquamation, NET formation, and thrombosis in a TLR2-dependent manner. SUMMARY:Mechanisms of erosion have received much less attention than those that provoke plaque rupture. Intensive statin treatment changes the characteristic of plaques that render them less susceptible to rupture. Thus, erosion may contribute importantly to the current residual burden of risk. Understanding the mechanisms of erosion may inform the development and deployment of novel therapies to combat the remaining atherothrombotic risk in the statin era.
Role of neutrophils in atherogenesis: an update.
Pende Aldo,Artom Nathan,Bertolotto Maria,Montecucco Fabrizio,Dallegri Franco
European journal of clinical investigation
BACKGROUND:The role of neutrophils in the beginning and the progression of the atherosclerotic process did not receive much attention until the last years. On the contrary, recent data, in both the experimental animals and humans, suggest important effects of these cells with possible clinical consequences. MATERIALS AND METHODS:This narrative review was based on the papers found on PubMed and MEDLINE up to July 2015. The search terms used were 'neutrophil, atherosclerosis' in combination with 'recruitment, chemokine, plaque destabilization and pathophysiology'. RESULTS:Different models demonstrate the presence and the actions of neutrophils in the early steps of the atherogenesis confirming the fundamental role of these cells in the response of the innate immune system to different pathogens (in this context the modified lipoproteins). However, also the late phases of the atherosclerotic process, in particular the destabilization of a mature plaque, seem to be modulated by the neutrophils, possibly through the interaction with recently discovered biological systems such as the endocannabinoids. CONCLUSIONS:The understanding of the mechanisms involved in the modulation exerted by neutrophils in atherosclerosis is pivotal in terms of the complete definition of the overall picture. This approach will certainly give us new targets and new pharmacological opportunities for the anti-inflammatory strategy of the cardiovascular prevention.
Emerging Associations Between Neutrophils, Atherosclerosis, and Psoriasis.
Sanda G E,Belur A D,Teague H L,Mehta Nehal N
Current atherosclerosis reports
PURPOSE OF REVIEW:Atherogenesis, once thought to be a passive process, is now recognized as a dynamic, immune-driven process. The critical innate immune cells, including neutrophils, normal-density granulocytes, and their newly identified subset low-density granulocytes, are moving to the forefront of interest in cardiovascular medicine due to their abundance in atherosclerotic plaques and chronic inflammatory diseases associating with early cardiovascular disease (CVD) such as psoriasis. In this review, we discuss the emerging roles of neutrophils in CVD and how they play a potential role in early CVD observed in psoriasis patients. This review aims to describe the roles of neutrophils in both early atherosclerosis and psoriasis. RECENT FINDINGS:Recent work has demonstrated mechanistic links between vascular inflammation and neutrophil frequency. Evolving mouse models and clinical trials targeting IL-17-associated pathways continue to elucidate contributions of neutrophils in both atherosclerosis and psoriasis. Early animal, in vitro and human studies suggest an important emerging role of neutrophils in atherosclerosis and psoriasis.
Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases.
Hoogeveen Renate M,Nahrendorf Matthias,Riksen Niels P,Netea Mihai G,de Winther Menno P J,Lutgens Esther,Nordestgaard Børge G,Neidhart Michel,Stroes Erik S G,Catapano Alberico L,Bekkering Siroon
European heart journal
A large number of cardiovascular events are not prevented by current therapeutic regimens. In search for additional, innovative strategies, immune cells have been recognized as key players contributing to atherosclerotic plaque progression and destabilization. Particularly the role of innate immune cells is of major interest, following the recent paradigm shift that innate immunity, long considered to be incapable of learning, does exhibit immunological memory mediated via epigenetic reprogramming. Compelling evidence shows that atherosclerotic risk factors promote immune cell migration by pre-activation of circulating innate immune cells. Innate immune cell activation via metabolic and epigenetic reprogramming perpetuates a systemic low-grade inflammatory state in cardiovascular disease (CVD) that is also common in other chronic inflammatory disorders. This opens a new therapeutic area in which metabolic or epigenetic modulation of innate immune cells may result in decreased systemic chronic inflammation, alleviating CVD, and its co-morbidities.
Monocytes, Macrophages, and Metabolic Disease in Atherosclerosis.
Flynn Michelle C,Pernes Gerard,Lee Man Kit Sam,Nagareddy Prabhakara R,Murphy Andrew J
Frontiers in pharmacology
Atherosclerotic cardiovascular disease (CVD) is a lipid-driven chronic inflammatory disease, in which macrophages are responsible for taking up these lipids and driving disease progression. Over the years, we and others have uncovered key pathways that regulate macrophage number/function and identified how metabolic disorders such as diabetes and obesity, which are common risk factors for CVD, exacerbate these pathways. This ultimately accelerates the progression of atherosclerosis and hinders atherosclerotic regression. In this review, we discuss the different types of macrophages, from monocyte-derived macrophages, local macrophage proliferation, to macrophage-like vascular smooth muscle cells, that contribute to atherosclerosis as well as myeloid-derived suppressor cells that may have anti-atherogenic effects. We will also discuss how diabetes and obesity influence plaque macrophage accumulation and monocyte production (myelopoiesis) to promote atherogenesis as well as an exciting therapeutic target, S100A8/A9, which mediates myelopoiesis in response to both diabetes and obesity, shown to be effective in reducing atherosclerosis in pre-clinical models of diabetes.
Vascular Macrophages in Atherosclerosis.
Xu Hailin,Jiang Jingxin,Chen Wuzhen,Li Wenlu,Chen Zhigang
Journal of immunology research
Atherosclerosis is the main pathological basis for the occurrence of most cardiovascular diseases, the leading global health threat, and a great burden for society. It has been well established that atherosclerosis is not only a metabolic disorder but also a chronic, sterile, and maladaptive inflammatory process encompassing both innate and adaptive immunity. Macrophages, the major immune cell population in atherosclerotic lesions, have been shown to play critical roles in all stages of atherosclerosis, including the initiation and progression of advanced atherosclerosis. Macrophages have emerged as a novel potential target for antiatherosclerosis therapy. In addition, the macrophage phenotype is greatly influenced by microenvironmental stimuli in the plaques and presents complex heterogeneity. This article reviews the functions of macrophages in different stages of atherosclerosis, as well as the phenotypes and functions of macrophage subsets. New treatment strategies based on macrophage-related inflammation are also discussed.
Disordered haematopoiesis and cardiovascular disease: a focus on myelopoiesis.
Dragoljevic Dragana,Westerterp Marit,Veiga Camilla Bertuzzo,Nagareddy Prabhakara,Murphy Andrew J
Clinical science (London, England : 1979)
Cardiovascular (CV) diseases (CVD) are primarily caused by atherosclerotic vascular disease. Atherogenesis is mainly driven by recruitment of leucocytes to the arterial wall, where macrophages contribute to both lipid retention as well as the inflammatory milieu within the vessel wall. Consequently, diseases which present with an enhanced abundance of circulating leucocytes, particularly monocytes, have also been documented to accelerate CVD. A host of metabolic and inflammatory diseases, such as obesity, diabetes, hypercholesteraemia, and rheumatoid arthritis (RA), have been shown to alter myelopoiesis to exacerbate atherosclerosis. Genetic evidence has emerged in humans with the discovery of clonal haematopoiesis of indeterminate potential (CHIP), resulting in a disordered haematopoietic system linked to accelerated atherogenesis. CHIP, caused by somatic mutations in haematopoietic stem and progenitor cells (HSPCs), consequently provide a proliferative advantage over native HSPCs and, in the case of loss of function mutation, gives rise to inflammatory plaque macrophages (i.e. enhanced interleukin (IL)-1β production). Together with the recent findings of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial that revealed blocking IL-1β using Canakinumab reduced CV events, these studies collectively have highlighted a pivotal role of IL-1β signalling in a population of people with atherosclerotic CVD. This review will explore how haematopoiesis is altered by risk-factors and inflammatory disorders that promote CVD. Further, we will discuss some of the recent genetic evidence of disordered haematopoiesis in relation to CVD though the association with CHIP and suggest that future studies should explore what initiates HSPC mutations, as well as how current anti-inflammatory agents affect CHIP-driven atherosclerosis.
The role of monocytosis and neutrophilia in atherosclerosis.
Chistiakov Dimitry A,Grechko Andrey V,Myasoedova Veronika A,Melnichenko Alexandra A,Orekhov Alexander N
Journal of cellular and molecular medicine
Monocytosis and neutrophilia are frequent events in atherosclerosis. These phenomena arise from the increased proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) and HSPC mobilization from the bone marrow to other immune organs and circulation. High cholesterol and inflammatory signals promote HSPC proliferation and preferential differentiation to the myeloid precursors (i.e., myelopoiesis) that than give rise to pro-inflammatory immune cells. These cells accumulate in the plaques thereby enhancing vascular inflammation and contributing to further lesion progression. Studies in animal models of atherosclerosis showed that manipulation with HSPC proliferation and differentiation through the activation of LXR-dependent mechanisms and restoration of cholesterol efflux may have a significant therapeutic potential.
CXCL4-induced macrophages in human atherosclerosis.
Domschke Gabriele,Gleissner Christian A
Atherosclerosis is considered an inflammatory disease of the arterial wall. Monocytes and monocyte-derived cells (most often termed macrophages) play an essential role in the formation of atherosclerotic lesions, as they take up lipids leading to subsequent foam cell formation accompanied by release of pro-inflammatory cytokines. Similarly, platelets have been discovered to represent an important cell type mediating inflammatory and immune processes in atherogenesis, mainly by secreting chemokines, which are stored in the platelets' alpha granules, upon platelet activation. Therefore, the interaction between monocyte-derived cells and platelets is of exceptional importance. In this review, we specifically focus on the chemokine (platelet factor-4, PF4) and its effects on monocytes and monocyte-derived cells. By formation of heterodimers dimers and -oligomers with CCL5, CXCL4 induces binding of monocytes cells to endothelial cell and thereby promotes diapedesis of monocytes into the subendothelial space. CXCL4 also affects the differentiation of monocytes as it induces a specific macrophage phenotype, which we suggested to term "M4". For example, CXCL4-induced macrophages irreversibly lose the hemoglobin-haptoglobin scavenger receptor CD163. The combination of CD68, S100A8, and MMP7 turned out to reliably identify M4 macrophages both in vitro and in vivo within atherosclerotic lesions. In human atherosclerotic plaques, M4 macrophages are predominantly present in the adventitia and the intima and their prevalence is associated with plaque instability suggesting that they are a marker of pro-inflammatory activity. Overall, CXCL4-induced M4 macrophages may represent a target for diagnostic and therapeutic interventions in human atherosclerotic disease.
Trained Innate Immunity as a Novel Mechanism Linking Infection and the Development of Atherosclerosis.
Leentjens Jenneke,Bekkering Siroon,Joosten Leo A B,Netea Mihai G,Burgner David P,Riksen Niels P
RATIONALE:There is strong epidemiological evidence for an association between acute and chronic infections and the occurrence of atherosclerotic cardiovascular disease. The underlying pathophysiological mechanisms remain unclear. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. It has recently been established that monocytes/macrophages can develop a long-lasting proinflammatory phenotype after brief stimulation with micro-organisms or microbial products, which has been termed trained immunity. OBJECTIVE:The aim of this study is to assess whether trained immunity mediates the link between infections and atherosclerotic cardiovascular disease. METHODS AND RESULTS:Brief exposure of monocytes to various micro-organisms results in the development of macrophages with a persistent proinflammatory phenotype: this represents a de facto nonspecific innate immune memory, which has been termed trained immunity. This is mediated by epigenetic reprogramming at the level of histone methylation and a profound rewiring of intracellular metabolism. Although this mechanism offers powerful protection against reinfection, trained macrophages display an atherogenic phenotype in terms of cytokine production and foam cell formation. Trained monocytes are present up to 3 months after experimental infection in humans. Moreover, a trained immunity phenotype is present in patients with established atherosclerosis. CONCLUSIONS:We propose that trained immunity provides the missing mechanistic link that explains the association between infections and atherosclerosis. Therefore, pharmacological modulation of trained immunity has the potential to prevent infection-related atherosclerotic cardiovascular disease in the future.
Monocytes and macrophages in atherogenesis.
Amengual Jaume,Barrett Tessa J
Current opinion in lipidology
PURPOSE OF REVIEW:Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid cells concerning their metabolic and phenotypic function is increasingly appreciated. This review summarizes the recent monocyte and macrophage literature and highlights how differing subsets contribute to atherogenesis. RECENT FINDINGS:Monocytes are short-lived cells generated in the bone marrow and released to circulation where they can produce inflammatory cytokines and, importantly, differentiate into long-lived macrophages. In the context of cardiovascular disease, a myriad of subtypes, exist with each differentially contributing to plaque development. Herein we describe recent novel characterizations of monocyte and macrophage subtypes and summarize the recent literature on mediators of myelopoiesis. SUMMARY:An increased understanding of monocyte and macrophage phenotype and their molecular regulators is likely to translate to the development of new therapeutic targets to either stem the growth of existing plaques or promote plaque stabilization.
The Role of Monocytes and Macrophages in Human Atherosclerosis, Plaque Neoangiogenesis, and Atherothrombosis.
Moroni Francesco,Ammirati Enrico,Norata Giuseppe Danilo,Magnoni Marco,Camici Paolo G
Mediators of inflammation
Atherosclerosis is one of the leading causes of death and disability worldwide. It is a complex disease characterized by lipid accumulation within the arterial wall, inflammation, local neoangiogenesis, and apoptosis. Innate immune effectors, in particular monocytes and macrophages, play a pivotal role in atherosclerosis initiation and progression. Although most of available evidence on the role of monocytes and macrophages in atherosclerosis is derived from animal studies, a growing body of evidence elucidating the role of these mononuclear cell subtypes in human atherosclerosis is currently accumulating. A novel pathogenic role of monocytes and macrophages in terms of atherosclerosis initiation and progression, in particular concerning the role of these cell subsets in neovascularization, has been discovered. The aim of the present article is to review currently available evidence on the role of monocytes and macrophages in human atherosclerosis and in relation to plaque characteristics, such as plaque neoangiogenesis, and patients' prognosis and their potential role as biomarkers.
Heterogeneity of atherosclerotic plaque macrophage origin, phenotype and functions: Implications for treatment.
Nagenborg Jan,Goossens Pieter,Biessen Erik A L,Donners Marjo M P C
European journal of pharmacology
Macrophages are key players in atherosclerotic lesions, regulating the local inflammatory milieu and plaque stability by the secretion of many inflammatory molecules, growth factors and cytokines. Monocytes have long been considered to be the main source of plaque macrophages. However, recent findings provide evidence for proliferation of local macrophages or transdifferentiation from other vascular cells as alternative sources. Recent years of research focused on the further identification and characterisation of macrophage phenotypes and functions. In this review we describe the advances in our understanding of monocyte and macrophage heterogeneity and its implications for specific therapeutic interventions, aiming to reduce the ever growing significant risk of cardiovascular events without any detrimental side effects on the patient's immune response.
Using High-Dimensional Approaches to Probe Monocytes and Macrophages in Cardiovascular Disease.
Dick Sarah A,Zaman Rysa,Epelman Slava
Frontiers in immunology
High dimensional approaches that characterize single cells at unprecedented depth have helped uncover unappreciated heterogeneity, a better understanding of myeloid cell origins, developmental relationships and functions. These advancements are particularly important in cardiovascular disease, which remains the leading cause of death worldwide. Gradual, monocyte-dependent inflammatory processes, such as the development of atherosclerotic plaque within arterial vessels, contrasts with the robust acute response within the myocardium that occurs when a vessel is occluded. Monocytes and macrophages differentially contribute to tissue injury, repair and regeneration in these contexts, yet many questions remain about which myeloid cell types are involved in a coordinated, organ-level sterile inflammatory response. Single cell RNA sequencing, combined with functional analyses have demonstrated that at least three populations of resident cardiac macrophages exist, and after tissue injury, there is significant diversification of the tissue macrophage pool driven by recruited monocytes. While these studies have provided important insights, they raise many new questions and avenues for future exploration. For example, how do transcriptionally defined sub-populations of cardiac macrophages relate to each other? Are they different activation states along a pre-defined trajectory of macrophage differentiation or do local microenvironments drive newly recruited monocytes into distinct functions? The answers to these questions will require integration of high-dimensional approaches into biologically relevant experimental systems to ensure the predicted heterogeneity possess a functional outcome.
Omega-3 fatty acids and leukocyte-endothelium adhesion: Novel anti-atherosclerotic actions.
Baker Ella J,Yusof M Hayati,Yaqoob Parveen,Miles Elizabeth A,Calder Philip C
Molecular aspects of medicine
Endothelial cells (ECs) play a role in the optimal function of blood vessels. When endothelial function becomes dysregulated, the risk of developing atherosclerosis increases. Specifically, upregulation of adhesion molecule expression on ECs promotes the movement of leukocytes, particularly monocytes, into the vessel wall. Here, monocytes differentiate into macrophages and may become foam cells, contributing to the initiation and progression of an atherosclerotic plaque. The ability of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) to influence the expression of adhesion molecules by ECs and to modulate leukocyte-endothelial adhesion has been studied in cell culture using various types of ECs, in animal feeding studies and in human trials; the latter have tended to evaluate soluble forms of adhesion molecules that circulate in the bloodstream. These studies indicate that n-3 PUFAs (both eicosapentaenoic acid and docosahexaenoic acid) can decrease the expression of key adhesion molecules, such as vascular cell adhesion molecule 1, by ECs and that this results in decreased adhesive interactions between leukocytes and ECs. These findings suggest that n-3 PUFAs may lower leukocyte infiltration into the vascular wall, which could contribute to reduced atherosclerosis and lowered risk of cardiovascular disease.
Inflammation in atherosclerosis.
Archives of cardiovascular diseases
Atherosclerosis is an inflammatory disease within the arterial wall that is responsible for several important adverse vascular events, including coronary artery disease, myocardial infraction, stroke and peripheral artery disease. Both innate and adaptive immunity play important roles in the development of atherosclerosis. In particular, monocytes/macrophages, which are the surrogate cells of innate immunity, have important proatherogenic effects. In addition, adaptive immune responses effected by T cells play important roles in atherosclerosis. While the T-helper cell type 1 (Th1) response has a potent proatherogenic effect, the pathogenic roles of other T cell subsets, such as the Th2 and Th17 pathways, remain controversial. However, the antiatherosclerotic protective roles of regulatory T cells and some Th2-related cytokines, such as interleukin-5, have been clearly established. In light of numerous data in animal models showing the importance of inflammatory cells in atherosclerosis and its complications, treatment of cardiovascular diseases with anti-inflammatory drugs may be an attractive strategy. However, future randomized placebo-controlled trials are required to test this possibility, to evaluate the proper effect of anti-inflammatory drugs as cardiovascular therapeutic agents without confounding effects.
Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy.
Hartman Joshua,Frishman William H
Cardiology in review
It has recently been appreciated that atherosclerosis is predominantly an inflammatory process. Atherosclerosis begins with a fatty streak, which is made up almost entirely of monocyte-derived macrophages. The development of an atheroma continues as T-cells, mast cells, and other inflammatory cells are recruited to the intima. This collection of inflammatory cells promotes smooth muscle cell replication and extracellular matrix elaboration, thereby increasing the lesion size. Various studies have highlighted that interleukin-6 (IL-6) is an upstream inflammatory cytokine that plays a central role in propagating the downstream inflammatory response responsible for atherosclerosis. IL-6 release is stimulated by acute infections, chronic inflammatory conditions, obesity, and physiologic stress. The high level of IL-6 found in such conditions has a myriad of functions, including hepatic synthesis of acute-phase reactants, activation of endothelial cells, increased coagulation, activation of the hypothalamic-pituitary-adrenal axis, and promotion of lymphocyte proliferation and differentiation. Considering the importance of IL-6 in the development of coronary artery disease, targeting its actions could prove to be beneficial. Individuals with a variant in the IL-6 receptor that impairs classic IL-6 signaling were found to have a decreased risk for coronary heart disease. Tocilizumab is a monoclonal antibody that targets the IL-6 receptor and has been show to alleviate symptoms in patients with rheumatoid arthritis, a disease largely driven by the proinflammatory actions of IL-6. Therefore, further studies are needed to determine the role of tocilizumab and other IL-6 receptor blockers in decreasing the inflammatory response key in the development of atherosclerosis.
[The inflammatory processes in atherogenesis].
Cichoń Natalia,Lach Dominika,Dziedzic Angela,Bijak Michał,Saluk Joanna
Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego
Atherogenesis is the process of atherosclerotic plaque formation, leading to coronary artery heart disease. This process involves immune cells, mainly T and B cells, monocytes and macrophages. The process of atherogenesis is induced by inflammatory damage of endothelial cells. The characteristic construction features of the atherosclerotic plaque is a predisposing factor for acute coronary syndromes. The accumulation of inflammatory cells in the artery inner membrane enhances the local inflammatory process due to the secretion of reactive oxygen species, inflammatory cytokines and metalloproteinases, which accelerate the development of atherosclerotic lesions in the arteries. In chronic inflammation of endothelial cells, which is atherosclerosis, there is a decrease in the concentration of elastin and collagen as a result of the increased apoptosis of smooth muscle cells of the intima. This reduces the integrity and strength of the fibrous cap that covers a layer of thrombogenic plaque from contact with blood elements. Permanent inflammation promotes the formation of necrotic core, composed of dead smooth muscle cells, macrophages and foam cells formed by phagocytosis of oxidized lipid molecules. The thin fibrous cap and a large necrotic core are the cause of plaque rupture and thrombus formation within the coronary artery.
Macrophage complexity in human atherosclerosis: opportunities for treatment?
Biessen Erik A L,Wouters Kristiaan
Current opinion in lipidology
PURPOSE OF REVIEW:The pivotal role of macrophages in experimental atherosclerosis is firmly established, but their contribution to human disease is less well defined. In this review we have outlined the current insights on macrophage phenotypes and their presumed precursors, monocytes, in clinical atherosclerosis, and their association with disease progression. Moreover, we will assess major clinical modifiers of macrophage-mediated plaque inflammation and define the outstanding questions for further study. RECENT FINDINGS:Our survey indicates that macrophage accumulation and status in human plaques are linked with lesion progression and destabilization as well as with symptomatic coronary artery disease. Likewise, levels of their precursors, circulating monocytes were repeatedly seen to associate with atherosclerosis and to predict clinical outcome. Furthermore, the presence and phenotype of both macrophages and monocytes appears to be responsive to the traditional risk factors of atherosclerosis, including hypercholesterolemia, hypertension, and type 2 diabetes, and to treatment thereof, with clear repercussions on disease development. SUMMARY:Although plaque macrophages and their precursor cells do represent attractive targets for treating cardiovascular diseases, this therapeutic avenue requires much deeper understanding of the complexity of macrophage biology in human atherosclerosis than available at present.
Macrophage: A Key Therapeutic Target in Atherosclerosis?
Taghizadeh Eskandar,Taheri Forough,Renani Pedram G,Reiner Željko,Navashenaq Jamshid G,Sahebkar Amirhossein
Current pharmaceutical design
BACKGROUND:Atherosclerosis is a chronic inflammatory disease and a leading cause of coronary artery disease, peripheral vascular disease and stroke. Lipid-laden macrophages are derived from circulating monocytes and form fatty streaks as the first step of atherogenesis. METHODS:An electronic search in major databases was performed to review new therapeutic opportunities for influencing the inflammatory component of atherosclerosis based on monocytes/macrophages targeting. RESULTS:In the past two decades, macrophages have been recognized as the main players in atherogenesis but also in its thrombotic complications. There is a growing interest in immunometabolism and recent studies on metabolism of macrophages have created new therapeutic options to treat atherosclerosis. Targeting recruitment, polarization, cytokine profile extracellular matrix remodeling, cholesterol metabolism, oxidative stress, inflammatory activity and non-coding RNAs of monocyte/macrophage have been proposed as potential therapeutic approaches against atherosclerosis. CONCLUSION:Monocytes/macrophages have a crucial role in progression and pathogenesis of atherosclerosis. Therefore, targeting monocyte/macrophage therapy in order to achieve anti-inflammatory effects might be a good option for prevention of atherosclerosis.
Inflammation and atherosclerosis: Cardiovascular evaluation in patients with autoimmune diseases.
Escárcega Ricardo O,Lipinski Michael J,García-Carrasco Mario,Mendoza-Pinto Claudia,Galvez-Romero Jose Luis,Cervera Ricard
Evidence now indicates that inflammation contributes considerably to the initiation and progression of atherosclerosis and active inflammatory processes may trigger plaque rupture and enhance the risk of coronary thrombosis leading to a clinical ischemic event. Interest in characterizing inflammatory markers that predict clinical events have dominated clinical investigation. Such markers include C-reactive protein, Fibrinogen and a number of interleukins. Human macrophages avidly phagocytize cholesterol crystals. These cholesterol crystals induce a dose-dependent secretion of mature Interleukin 1-beta (IL-1β) from human monocytes and macrophages (an NLRP3 inflammasome-mediated pathway). Since IL-1β production leads to increased levels of IL-6 and C-reactive protein, this could be a mechanistic link between early deposition of cholesterol crystals within the vessel wall to the macrophage-monocyte interactions that initiate fatty streaks and promote local atherosclerotic progression. We have entered a time where a pure anti-inflammatory drug without significant effects on lipids or any other traditional cardiovascular risk factor decreased cardiovascular events. Patients with autoimmune diseases are at increase cardiovascular risk. In this review we describe the link between inflammation and atherosclerosis. Furthermore we explore the data regarding primary prevention, cardiac imaging for risk stratification and the implications of targeting inflammation in patients with autoimmune disease.
Monocyte subsets in atherosclerosis.
Hristov M,Heine G H
Endothelial dysfunction and chronic inflammation of the arterial wall continuously drive the development of atherosclerotic lesions. Monocytes, as cells of the innate immunity, are particularly involved in this process. In the last decade, heterogeneity of circulating monocytes has widely been acknowledged, and a recent consensus nomenclature subdivides classical, intermediate and nonclassical monocytes. Accumulating experimental and clinical data suggest a differential, subset-specific contribution of monocytes to the pathology of atherosclerosis. This review summarizes recent key findings on human and mouse monocyte subpopulations, specifically highlighting their phenotype, functional characteristics and mechanisms of recruitment at homeostatic conditions, in atherosclerotic vascular disease, and after acute myocardial infarction.
White blood cell counts, leukocyte ratios, and eosinophils as inflammatory markers in patients with coronary artery disease.
Kounis Nicholas G,Soufras George D,Tsigkas Grigorios,Hahalis George
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count has emerged as a marker of inflammation that is widely available in clinical practice. Since inflammation plays a key role in atherosclerosis and its end results, discovering new biomarkers of inflammation becomes important in order to help diagnostic accuracy and provide prognostic information about coronary cardiac disease. In acute coronary syndromes and percutaneous coronary intervention, elevated levels of almost all subtypes of white blood cell counts, including eosinophils, monocytes, neutrophils, and lymphocytes, and neutrophil-lymphocyte ratio and eosinophil-leukocyte ratio constitute independent predictors of adverse outcomes. Eosinophil count and eosinophil-leukocyte ratio, in particular, emerge as novel biomarkers for risk stratification in patients with coronary artery disease. Since the presence of eosinophils denotes hypersensitivity inflammation and hypersensitivity associated with Kounis syndrome, this reality is essential for elucidating the etiology of inflammation in order to consider predictive and preventive measures and to apply the appropriate therapeutic methods.
The Role of Inflammation in Cardiovascular Outcome.
Montecucco Fabrizio,Liberale Luca,Bonaventura Aldo,Vecchiè Alessandra,Dallegri Franco,Carbone Federico
Current atherosclerosis reports
PURPOSE OF REVIEW:The aim of this review is to update the pathophysiological role of innate immune response in the cardiovascular (CV) disease outcomes, particularly focusing on coronary atherosclerosis and heart failure. RECENT FINDINGS:Inflammatory processes comprised with the innate immunity reaction are believed to actively trigger CV disease development and final clinical events. For instance, by releasing proteases and neutrophil extracellular traps, neutrophil recruitment and activation might strongly influence atherosclerotic plaque stability. Similarly, neutrophils drive the early inflammatory response following a myocardial infarction. However, these cells contribute themselves to infarct healing by orchestrating monocyte/macrophage recruitment and polarization within the ischemic myocardium. Given their heterogeneity and plasticity, the balance between recruitment, proliferation, and polarization of monocyte/macrophage is a further leading determinant of advanced plaque maturation. Moreover, timely shift from a pro-inflammatory to a resolving macrophage phenotype may influence cardiac remodeling as well as development of heart failure (HF). Alongside macrophage recruitment and activation into the remote, non-ischemic myocardium also contributes to cardiac remodeling and HF development. Innate immune response is a tightly regulated process where a timely modulation of the balance between damaging and resolving properties critically impacts on CV outcome. Further progress may improve the determination of the prognostic relevance of inflammatory biomarkers on clinical CV outcome.
The Link Between Inflammatory Disorders and Coronary Heart Disease: a Look at Recent Studies and Novel Drugs in Development.
Teague H,Mehta Nehal N
Current atherosclerosis reports
Inflammation is a critical component in the development of coronary heart disease (CHD), specifically in the process of atherogenesis. Human translational and preclinical studies have demonstrated that inflammation contributes to the development, sustainment, and progression of atherosclerosis, and epidemiological studies demonstrate that human diseases associated with increased systemic inflammation increase the risk of CHD-related events. Therefore, over the last decade, multiple clinical studies were designed to target the inflammatory cascade in order to reduce the risk of CHD and to identify which populations may benefit from these preventative treatment strategies. This review briefly summarizes inflammation as a risk factor in atherosclerosis, human disease states associated with accelerated atherosclerosis, and current treatment strategies for CHD targeting the inflammatory cascade.
Role of Allergic Inflammatory Cells in Coronary Artery Disease.
Niccoli Giampaolo,Montone Rocco A,Sabato Vito,Crea Filippo
Inflammation is an important player both for the initiation and progression of coronary artery disease and for coronary plaque instability. Moreover, inflammation contributes to stent thrombosis and in-stent restenosis after percutaneous coronary intervention. In the past several decades, most studies evaluated the involvement of cellular effectors of classic inflammatory responses, such as monocytes/macrophages, neutrophils, and T cells. Yet, besides classic inflammation, mounting evidence derived from both experimental and clinical studies suggests an important, often unrecognized, role for effector cells of allergic inflammation in both the pathogenesis of coronary artery disease and adverse events following stent implantation. In this review, we discuss the role of effector cells of allergic inflammation in the setting of coronary artery disease progression and instability, and in the occurrence of adverse events following stent implantation, as well. Moreover, we discuss possible therapeutic approaches targeting different specific pathways of allergic inflammatory activation.