Role of Monocytes in Heart Failure and Atrial Fibrillation

HomeJournal of the American Heart AssociationVol. 7, No. 3Role of Monocytes in Heart Failure and Atrial Fibrillation Open AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessReview ArticlePDF/EPUBRole of Monocytes in Heart Failure and Atrial Fibrillation Farhan Shahid, MRCP, Gregory Y.H. Lip, MD and Eduard Shantsila, PhD Farhan ShahidFarhan Shahid Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom , Gregory Y.H. LipGregory Y.H. Lip Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark and Eduard ShantsilaEduard Shantsila Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom Originally published1 Feb 2018https://doi.org/10.1161/JAHA.117.007849Journal of the American Heart Association. 2018;7:e007849IntroductionHeart failure (HF) is a culmination of pathological processes presenting with debilitating symptoms that highlight a complex interplay between immunological, hormonal, and metabolic systems resulting in impaired cardiac function. HF has a major impact on the quality of life and longevity of the affected patients.1 Inflammation has been shown to play a pivotal role in the pathogenesis of HF within animal studies, but there has been limited translation of these findings into human research.2, 3Monocytes and monocyte‐derived macrophages play a role in the development of HF. In human immunology, monocytes undertake phagocytosis to provide protection from foreign pathogens such as bacteria and viruses. Nevertheless, there are distinct subsets of monocytes with potential for beneficial or detrimental effects on HF pathogenesis, although intimate details of the involved processes are not yet fully determined.4, 5 Of importance is the fact that the role of monocytes in cardiovascular diseases is complex and includes inflammation, which subsequently contributes to processes of regeneration, repair, and modulation of the prothrombotic state.6, 7 All these functions are highly relevant to patients with HF, who show progressive impairment of cardiac function and frequently develop atrial fibrillation (AF), an arrhythmia with a high risk of thrombotic complications.Therefore, of equal interest is the role of the immune system in AF, a very common arrhythmia in HF, which has been strongly linked to inflammation.8 Atrial and ventricular fibrosis have been documented in patients with AF, with monocytes playing a role in these processes, based on animal studies.9, 10 Indeed, inflammation in the myocardium clearly predisposes to cardiac fibrosis.11Why is this important? Cardiac fibrosis is an active process that is part of the remodeling of the myocardium in response to mechanical, chemical, and electrical stressors, along with the inflammation.12 Myocardial fibrosis reduces left ventricular (LV) compliance and increases filling pressures and atrial load. This, in turn, promotes LV and atrial fibrosis, predisposing to AF and thus completing the vicious circle.13 HF and AF should therefore not necessarily be considered as pathophysiologically unrelated entities, and indeed the pathological/inflammatory processes underpinning both conditions seem to overlap and this may, in turn, guide therapeutic options.The aim of this review article is to identify the role of monocytes and their associated inflammatory cells in the pathogenesis of cardiac fibrosis. Particular focus is given to monocyte subsets and their associated immune response cells in the inflammation process of HF and AF. Considerations on possible therapeutic targets related to these cells in the treatment of HF are also discussed.Etiology and Pathogenesis of HFA wide range of cardiac conditions, inherited defects, and systemic disorders contribute to the pathogenesis of HF. Ischemic heart disease is a major cause of HF attributed to chronic ischemia (atherosclerosis/coronary calcification) and acute myocardial necrosis (atherothrombosis).14 Hypertensive cardiac disease leads to the mechanical myocardial stress and neurohormonal changes that are detrimental to cardiac myocytes. Definitive studies have not only found significant lifetime risk of HF in people with blood pressure of over 160/90, but also provided evidence of improved blood pressure control contributing to reduced incidence of HF.15, 16 Valvular heart disease plays a lesser role as a cause of HF in the developed world attributed to improved living conditions and medical and surgical therapy. Globally, however, rheumatic heart disease is still a major cause for HF.17LV dysfunction secondary to myocardial infarction (MI) is the most studied HF etiology. Cardiac remodeling post‐MI includes stretching of cardiac myocytes attributed to the raised intraventricular pressures found in acute cardiac ischemia.18 The noninfarcted myocardium attempts to compensate for the area of myocardial loss. Remodeling of the unaffected myocardium is a consequence of the expanding myocardial collagen scar, as well as the response to neuroendocrine stimuli and increased wall stress.18MI is accompanied by an inflammatory process, involving the migration of macrophages, monocytes, and neutrophils into the necrotic and ischemic areas. The subsequent signaling cascade and neurohormonal activation is responsible for the recruitment of inflammatory cells to site of tissue injury.19The early phase of postinfarct remodeling (within 72 hours) predominantly involves the infarct zone itself and can be associated with the zone expansion. Late remodeling involves the left ventricle globally and is associated with dilatation, changes in ventricular morphology, and hypertrophy. Adverse remodeling leads to cardiac failure attributed to inability to prevent or reverse progressive ventricular dilatation, expansion of the myocardial scar, and deterioration in contractile function.20The role of monocytes/macrophages in postinfarct remodeling has been demonstrated in numerous studies.19, 21, 22 There exists a fine balance between excessive and prolonged infiltration of inflammatory macrophages into the infarct myocardium, causing a detrimental inflammatory response with subsequent cardiac fibrosis, dysfunction, and adverse ventricular remodeling.23, 24 In contrast, monocytes/macrophages are also essential to wound healing and tissue repair through phagocytosis, angiogenesis, and favorable remodeling of the extracellular matrix in the infarcted area.4 It remains unclear how the balance of contrasting roles of monocyte/macrophages is achieved. However, the role of monocyte subset populations may be a logical explanation for the diversity in function.The hypothesis of monocyte subset heterogeneity and function in MI is formed on the basis of their role in modulating chemokine expression in mice, which, in turn, recruit Ly‐6Chigh and Ly‐6Clow monocyte subset through C‐C chemokine receptor type 2 (CCR2) and C‐X3‐C motif chemokine receptor (CX3CR) 1, respectively. Ly‐6Chigh monocytes dominate early and exhibit a proinflammatory function. Ly‐6Clow monocytes dominate later. Ly‐6Clow monocytes promote myocardial healing through myofibroblast accumulation, angiogenesis, and collagen deposition.4Therefore, targeted therapy toward monocyte subsets is an attractive therapeutic option to facilitate favorable cardiac remodeling. The existence of monocyte/macrophage subset heterogeneity and their step‐wise contribution to cardiac remodeling provides an opportunity for specific target intervention in the future.What Do Monocytes Do?Monocytes are a type of white blood cell present in the peripheral circulation. The primary roles of monocytes are in the participation of innate immunity and to maintain or replenish different types of macrophages and dendritic cells, which aid in phagocytosis of pathogens.25 Monocytes make up to 8% of the peripheral blood white cells and play a central role in the host response to exogenous and endogenous pathogen species, such as bacteria and viruses. Additionally, they modulate the inflammatory processes, producing both pro‐ and anti‐inflammatory cytokines and developing macrophages with pro‐ and anti‐inflammatory phenotype.26Monocytes are derived from macrophage dendritic cell precursors that originate from the bone marrow under normal homeostatic conditions. Common myeloid progenitor cells, derived from the bone marrow, are responsible for differentiation of precursor progenitor cells into monocytes.26 Macrophage dendritic cell precursors mature to form either dendritic cells or macrophages. This process is dependent upon stimulation by cytokines and/or microbial molecules.27 Evidence to date suggests that both monocytes and dendritic cells diverge at a very early multipotent progenitor stage.26 Common myeloid progenitor cells give rise to the granulocyte‐macrophage lineage, which, in turn, give rise to macrophage dendritic cell precursors and subsequently, the committed monocyte precursor.28 Control of monocyte/macrophage differentiation is guided by a multitude of transcription factors, the complexity of which is beyond the scope of this review article.29In the 1970s, studies highlighted the increase in monocyte proliferation within the bone marrow in response to inflammatory stimuli, allowing for monocytosis.30 During steady state, circulating monocytes have a half‐life of ≈3 days.31 Monocytes are mobilized from the bone marrow at times of tissue injury and differentiate into macrophages or dendritic cells while mounting an immune response. However, they are also implicated in diseases with proinflammatory shift such as heart failure and atherosclerosis.32, 33 Multiple animal studies have shown a diverse and complex function of monocytes depending upon the inflammatory environment, central to which is the ability of monocytes to be mobilized to site of injury.34With regard to atherosclerosis, monocyte‐derived "foam cell" macrophages act as a substrate and thus facilitate the progress to MI. Monocyte counts are further highly increased in other forms of acute cardiovascular pathology.2, 33, 35Overall, monocytes have been used as indicators of prognosis in humans, with their high numbers being associated with increased risk of recurrent MI, hospitalization, and cardiac death. Available data indicate that monocyte mobilization in acute cardiac disease does not simply reflect response to cardiac damage, but its active involvement in the pathological process.5, 36Human Monocyte HeterogeneityMonocyte subsets were first isolated in 1988 using flow cytometry.37 Expression of CD14 (lipopolysaccharide receptor) and CD16 (Fc receptor) is used to define human monocyte subsets. It should be noted that changes in expression of monocyte subsets are limited to cell‐surface protein expression assessed by flow cytometry, with changes in gene expression being up‐ or downregulated dependent on functional properties.38Human monocyte subsets do not follow their mouse counterparts, in which initial studies in this field were undertaken. As such, nomenclature for human and mouse monocytes is not directly interchangeable and thus should not be directly compared. Human monocytes do not express Ly6C and description of their subsets is primarily based on expression of CD14 (lipopolysaccharide receptor) and CD16 (FC gamma III receptor; Table 1).39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51Table 1. Phenotypic and Functional Differences Between Monocyte SubsetsHuman (Mon1)Mouse (Mon1)Human (Mon2)Mouse (Mon2)Human (Mon3)Mouse (Mon3)Proportion of total monocytes, %39, 408540 to 4555 to 321026 to 50Functional properties39, 40, 41High phagocytic activityHigh phagocytic activity, proinflammatoryHigh phagocytic activity. T‐ cell proliferation and stimulation, angiogenesis, superior ROS productionHigh phagocytic activity, proinflammatoryLow phagocytic activity, high "patrolling" activity (in vivo), T‐cell proliferation and stimulationLow phagocytic activity, patrolling function, tissue repairSurface markers present39, 42, 43, 44CD62L, CCR2, CLEC4D, CLEC5A, IL13Rα1, CXCR1, CXCR2CCR2, CD11b, CD115, CCR5CCR2, CD74, HLA‐DR, Tie‐2, ENGCCR2, CD11b, CD115Siglec10, CD43, SLANCX3CR1, CD11b, CD115, CCR5Surface markers absent39, 41, 45CX3CR1, CD123, p2rx1, Siglec10CX3CR1 (low)CD62L, CXCR1, CXCR2, CLEC4D IL13Rα1CX3CR1 (low)CCR5, CD62L, CXCR1, CXCR2, CD163, CLEC4D, IL13Rα1CCR2 (low)Response to LPS39, 42, 46, 47, 48IL‐10, G‐CSF, CCL2, RANTES, IL‐6, IL‐8ROS, TNFα, nitric oxide, IL‐1β, IL10 (low levels), IFN‐1, VLA‐4, IL‐6, CD62LIL‐6, IL‐8ROS, TNFα, nitric oxide, IL‐1β, IL10 (low levels), IFN‐1, VLA‐4, IL‐6, CCR7, CCR8TNFα, IL‐1β, IL‐6, IL‐8IL‐10 (high levels)Increased gene expression28, 39, 42, 49, 50, 51Wound healing and anticoagulation, S‐100 proteins, scavenger receptors, C‐type lectin receptors, antiapoptosis, response to stimuli (CCR2, THBS1, CD163, RNASE4, EDG3, S100A12, CLEC4D, VEGFA, F5, RNASE2, RNASE6, F13A1, CRISPLD2, PLA2G7CES1, EREG, QPCT)CD177, FN1, Sell, Mmp8, F13a1, Atrnl1, Ly‐6c, Chi313MHC Class II, presentation and processing (CD14, CSPG2, SLC2A3, CD9, CD163, PLA2G7, MCEMP1, CLEC10A, EVA1, RNASE2, GFRA2, ALDH1A1, GALS2, MARCO, ALOX5AP, S100A12, QPCT, FOLR3, OSM, EGR1, CYP27A1, OLFM1, PAD14, HLADOA, ANG, H19, SCD, calgranulin B, S100A9DDIT4Inconclusive dataCytoskeletal arrangement, complement components, proapoptosis, downregulation of transcription (FMNL2, CDKN1C, FCGR3A/B)Vegfc, G0s2, Ikzf3, Tgfbr3, Cd83, Eno3, Tgm2, Itgax, CD36, Dusp16, Slc12a2, Fabp4Human monocytes are dominated by "classical" CD14++CD16− (Mon1) monocytes (ie, 85%). Humans have at least 2 types of nonclassical monocytes. The CD14++CD16+ (Mon2) subset makes up around 6% of monocytes in humans. CD14+CD16++ (Mon3) human monocytes make up 9% of all monocytes.4, 52 There are many significant differences between Mon2 and Mon3, and, overall Mon2 is phenotypically and functionally closer to Mon1 than to Mon3 (discussed in more detail below). Earlier studies analyzed these 2 subsets together, and such data need to be interpreted with care.A consensus opinion on the nomenclature of human monocytes in 2010 classed monocyte subsets as classical (CD14++CD16−), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++).53 However, to avoid ambiguity the phenotypic definition and numerical designation (ie, Mon1, Mon2, and Mon3) have been incorporated into the most recent consensus document on monocytes subsets.54Although direct correlation between human monocyte subsets is difficult, their differentiation and role in innate immunity are comparable. In fact, both Mon2 and Mon3 have reduced phagocytic activity, reduced production of reactive oxygen species along with lower levels of CCR2 expression.55 Several studies have highlighted the presence of raised levels of Mon2 in human inflammatory diseases.56Mon1 is characterized by high expression of CD14, interleukin (IL)‐6 receptor, CD64, CCR2, and CD163, with less‐dense expression of vascular cell adhesion molecule and CD204. Intracellular adhesion molecule receptor, C‐X‐C chemokine receptor type 4, CD163, and vascular endothelial growth factor receptor 1 have the highest expression on Mon2. Mon3 has maximal expression of CD16, vascular cell adhesion molecule 1 receptor, and CD204, with much lower expression of CD14, IL‐6 receptor, CD64, CCR2, and CD163 that Mon257 (Table 2).42, 55, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87Table 2. Differential Expression of Surface Markers Between Monocyte SubsetHumanMouseMon1Proportion of total monocytes, %39853940 to 4539Functional properties39High phagocytic activity39High phagocytic activity, proinflammatory39Surface markers/receptors presentCD1449, 58HighHighCD1649, 58LowLowCCR259, 60, 61High (increased 26‐fold)HighCX3CR149, 55, 59, 60LowLowCXCR149, 55, 62High (increased 5‐fold)LowCXCR249, 62High (increased 7‐fold)–CD11b49, 61, 63, 64, 65LowHighCD11549, 66–HighCD62L49, 58, 65High (increased 3‐fold)HighCLEC4D49, 67High (increased 4‐fold)–CLEC5A42, 49, 67High (increased 3‐fold)–IL13Rα149High (increased 9‐fold)–CD5449, 68Low (decreased 2‐fold)–CD4049, 65High (increased 6‐fold)–CD3642, 49, 69High (increased 2‐fold)–CD9949, 70High (increased 2‐fold)–CCR149, 71High (increased 2‐fold)–P2XR149Low (4‐fold)–HLA‐ABC49, 72Low (decreased 1‐fold)–CLEC10A49Low (decreased 6‐fold)–GFRA249Low (decreased 6‐fold)–HLA‐DR42, 49, 72, 73Low (decreased 8‐fold)–CD16349, 74, 75Low (decreased 1‐fold)–CD11545, 49, 76Low (decreased 1‐fold)HighSLAN49, 77, 78High (increased 2‐fold)–CD1d49High (increased 1‐fold)–CCR549, 79, 80Low (decreased 1‐fold)–CD29449Low (decreased 1‐fold)–Siglec1049, 81, 82Low (decreased 7‐fold)–Mon2Proportion of total monocytes, %5395 to 3239Functional propertiesHigh phagocytic activity, T‐cell proliferation and stimulation, angiogenesis, superior ROS production39High phagocytic activity, proinflammatory39Surface markers/receptors presentCD1442, 49, 58HighHighCD1642, 49, 58LowLowCCR249, 60, 83High (increased 8‐fold)HighCX3CR149, 55, 60LowLowCXCR149, 55, 62High (increased 4‐fold)LowCXCR246, 49, 62High (increased 3‐fold)–CD11b49, 61, 65HighHighCD11542, 45, 49LowHighCD62L49, 65, 72High (increased 1.3‐fold)–CLEC4D49High (increased 18‐fold)–CLEC5A42, 49High (increased 5‐fold)–IL13Rα149High (increased 2‐fold)–CD5449, 68High (increased 1‐fold)–CD4049, 65High (increased 1‐fold)–CD3649, 69High (increased 5‐fold)–CD9949, 70High (increased 5‐fold)–P2XR149Low (decreased 5‐fold)–HLA‐ABC49, 72High (increased 1‐fold)–CLEC10A49High (increased 4‐fold)–GFRA249High (increased 3‐fold)–HLA‐DR49, 72, 73High (increased 2‐fold)–CD16349, 75High (increased 6‐fold)–SLAN49, 77, 78Low (decreased 3‐fold)–CD1d49Low (decreased 5‐fold)–CCR549, 79, 80High (increased 7‐fold)–CD29449Low (decreased 3‐fold)–Siglec1049, 81, 82Low (decreased 21‐fold)–Mon3Proportion of total monocytes, %103926 to 5039Functional propertiesLow phagocytic activity, high "patrolling" activity (in vivo), T‐cell proliferation and stimulation39Low phagocytic activity, patrolling function, tissue repair39Surface markers/receptors presentCD1449, 58LowLowCD1649, 58HighHighCCR249, 60, 61LowLow/–CX3CR145, 49, 60, 65HighHighCD11b49, 61, 84HighHighCD62L58, 65, 85LowLowP2XR149High (increased 1.2‐fold)–HLA‐ABC49, 72Low (–)–CLEC10A49Low (–)–GFRA249Low (–)–HLA‐DR49, 72, 73Low (–)–CD16349, 74, 86High (increased 7‐fold)–CD11545, 49, 76Low (decreased 2‐fold)HighSLAN49, 77, 78, 87Low (decreased 7‐fold)–CD1d49High (increased 4‐fold)–CCR549, 79, 80High (increased 8‐fold)–CD29449Low (decreased 2‐fold)–Siglec1049, 81, 82Low (decreased 3‐fold)–(–) indicates evidence lacking or under‐reported.Monocyte subpopulations differ in the range of cytokines they can produce in response to stimulation. Mon1 has been shown to preferentially express cytokines IL‐1β, IL‐6, monocyte chemoattractant protein 1 (MCP‐1), an inhibitor of nuclear factor kappa β Mon2 anti‐inflammatory Mon3 production in response to than further the functional differences between monocyte However, recent specific of IL‐6 and cytokines by Mon2 and Mon3 in response to (Table Differential by Monocyte in to in Human and to 49, 49, 49, 65, 49, 49, 65, indicates C‐C chemokine receptor type G‐CSF, RANTES, on normal cell and necrosis factor Monocyte mouse monocyte subsets were based on the expression of a chemokine receptor, CCR2 to monocytes a and with cells, most being studied in postinfarct cardiac Differential expression of an inflammatory monocyte for mouse subset of the 2 mouse monocyte subsets and is used in there is evidence for the existence of a subset with intermediate which human Mon2 The subsets differ in expression of for and have a high of CCR2 and only numbers of are present on monocytes. In contrast, monocytes CCR2, but express high levels of monocytes have phagocytic and proinflammatory In acute MI, they in of myocardial along with macrophages a proinflammatory monocytes, on the other have been found to have anti‐inflammatory and this subset promotes post‐MI myocardial healing through the processes of angiogenesis, and collagen the subset is associated with detrimental effects to myocardium and their high levels in the acute phase of MI myocardial studies have demonstrated that cells reactive oxygen species, nitric oxide, and inflammatory cytokines necrosis factor in response to The subset migration is through the CCR2 receptor that a in the for vascular cell adhesion molecule 1 have found that monocytes preferentially into the of vascular inflammation and CCR2 is central to this process, also the subset toward macrophage the of inflammation, into which in the to vascular using In response to cells anti‐inflammatory cytokines The response to inflammation the differentiation of monocytes into macrophages, which, in turn, anti‐inflammatory cytokines central to tissue of Monocyte the and subsets are present in the bone Mon1 the bone marrow, the peripheral through CCR2 chemokine studies the ability of Mon1 to differentiate further into Mon2 upon migration from the bone marrow, which the recent studies have shown the initial of Mon1 in response to with the subsequent differentiation into Mon2 and Mon3 However, of bone marrow indicates that cells with Mon2 are present in human bone In fact, cells with the Mon2 were the cells within the bone numbers have been found to follow a by which is a gene in the In to the presence of CCR2 present on monocytes the of patrolling monocytes is dependent upon the receptor for the of which leads to an inability of Mon3 to from the bone inflammatory conditions HF, MI, and mouse have shown the to be of of monocytes from the is dependent upon as to CCR2 in the bone in cardiovascular there is a upon a chemokine 1, to direct the of monocytes from both the and bone marrow of Monocyte studies involving gene highlight the expression of involved in angiogenesis, wound and Mon1 have a to produce and in response to During the inflammatory process, both Mon1 and Mon2 to thus allowing monocytes to into human tissue and the inflammatory contrast, Mon3 to through the functional 1, subsequently the of and has been implicated in conditions, such as of Monocytes in Cardiovascular and Heart plays a pivotal role in the pathogenesis of HF. such as IL‐6 and TNFα, are markers of active disease and of the myocardium has from ischemic heart cardiac and metabolic which is a of has been found to be in patients with HF and this is to be a of monocyte of cells to the site of tissue injury upon specific cell‐surface monocytes and cell adhesion that to signaling by cytokines from the the monocytes differentiate into macrophages, which promote tissue The complex within myocardial cells to of both pro‐ and anti‐inflammatory In pathological conditions, there is an of tissue and inflammation leads to the of macrophages, which, of healing cause tissue with adverse remodeling. to the monocyte/macrophage balance is a logical therapeutic under specific stimuli monocytes differentiate into macrophages. play a role in the phagocytosis and of inflammation to can cause to the vascular activation of tissue and activation of migration of cells to the of the thus the process of and myocardial necrosis an inflammatory process in the myocardium, which involves activation of cells, in turn, are of producing and growth In patients with who an MI, Mon2 subsets were and their high counts recurrent cardiovascular and ischemic HF, Mon1 have counts to with disease HF, but their numbers are increased HF In contrast, Mon2 is the only subset increased in patients with HF and a further increase in acute Of high Mon2 counts were associated with in that using a of and This suggests a presence of of this subset in patients with of their functional not analyzed in the and is to be possible or associated with the is on the role of Mon3 in HF given that both their or were This may be attributed to differences in of the studied for an of Mon3 in patients with HF, as in the with HF etiology. in studies is the of control for that may be responsible for the of monocytes. this potential should still the importance of monocytes in the inflammatory process that in HF with further in human on Mon2 being myocardium provides stimuli for monocyte recruitment in patients with HF. The presence of excessive LV and atrial in studies of with HF with on the of has shown to myocardial macrophages to the monocyte Monocyte recruitment is further by the presence of tissue and (Table in Mon2 and Mon3 in Cardiovascular myocardial with correlation with (in with risk heart raised to heart with