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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Circ Res. Author manuscript; available in PMC Jun 7, 2014.
Published in final edited form as:
PMCID: PMC3753681
NIHMSID: NIHMS490726

Monocyte and macrophage heterogeneity in the heart

Abstract

Monocytes and macrophages are innate immune cells that reside and accumulate in the healthy and injured heart. The cells and their subsets pursue distinct functions in steady state and disease, and their tenure may range between hours to months. Some subsets are highly inflammatory, while others support tissue repair. This review discusses current concepts of lineage relationships and systems’ cross talk, highlights open questions, and describes tools for studying monocyte and macrophage subsets in the murine and human heart.

Keywords: heart failure, myocardial infarction, healing, monocyte, macrophage

INTRODUCTION

Myocardial infarction inflicts a wound to the heart, which -- from the perspective of basic biology -- shares many features with wounds resulting from trauma or surgery. A parallel between both is that the initial injury, no matter whether traumatic or ischemic, initiates a general healing response of the body, which involves many organ systems in the task of restoring equilibrium and ensuring survival. Unlike many wounds resulting from trauma, MI is a form a sterile injury. Another distinction is that the wound in the heart is constantly subjected to the considerable strain of cardiac contractions. Likely, myocardial infarction is one of the most frequent wounds in the USA, as coronary syndromes occur once every 25 seconds1. Certainly, it is one of the most lethal wounds. If it does not kill immediately, myocardial infarction may result in heart failure, a syndrome with high mortality1. Increasingly, we understand that the healing process in the weeks after ischemia paves the road to either recovery or left ventricular dilation. Insufficient healing may lead to infarct expansion and trigger left ventricular remodeling. However, no therapeutic measures exist in the clinic to propagate healing and prevent heart failure. Immediate reperfusion therapy may save heart muscle, and heart failure medication prolongs the life of infarct patients. Wound healing that occurs after ischemic injury and may result in heart failure should be explored from a perspective of the recent advances in understanding leukocyte biology. In particular, the improved knowledge on the role of monocytes, macrophages and their subsets in steady state and disease created new insight into heart failure evolution post-MI. Macrophages reside in the healthy heart, and while they may not be as frequent as myocytes, endothelial cells and fibroblasts, their numbers are substantial2, and increase during disease3, 4. Their functions, especially in the steady state and the remote zone after MI, remain elusive. Our review article focusses on these protagonist immune cells and examines their subsets, source, phenotype, fate and function in the steady state and disease. We will discuss monocytes’ and macrophages’ potential interaction with parenchymal cells in the heart while paying attention to other organ systems that are involved in cardiovascular disease.

Monocytes and macrophages

The existence of monocytes has been appreciated since at least the 1920s5. The idea that monocytes derive from bone marrow precursors, circulate, and give rise to tissue macrophages was consolidated in the 1960s and has dominated much of our thinking since6. A major characteristic of the model is that macrophage development follows a linear and spatially-restricted trajectory. The model has been influential for what it proposes but also for what it excludes. Restricting promonocytes to the bone marrow, monocytes to the blood, and macrophages to the tissue precludes the existence of promonocytes outside the bone marrow, monocytes outside the blood, and macrophages outside tissue. Many studies, some also dating back to the 1960s, have provided evidence against these locational and ontogenic restrictions7, 8. Precursors can develop and give rise to monocytes outside the bone marrow in a process called extramedullary monocytopoiesis9, 10. The phenomenon is rare in the steady state, increases during inflammation, and illustrates a previously unappreciated dynamic of cellular relocation. Studies have also shown that monocytes are not exclusively circulating but can reside in tissue as reservoirs for mobilization during inflammation11. Moreover, there are vast transcriptional differences between classical macrophage populations in various tissues12. We may therefore need to re-examine, at the functional level, in what ways various macrophages differ, and in what ways they are similar.

Recent studies show that many tissue macrophages in the steady state do not derive from monocytes but from progenitors that have seeded tissue from the yolk sac prior to the development of definitive hematopoiesis13-17. The work builds on earlier studies that argued for the dual development of macrophages in the spleen8, but also provides mechanistic insight, showing the specific involvement of transcription factors Pu-1 and Myb. The non-hematopoietic origins of macrophages in tissues such as brain, liver, lung, and spleen, raises a plethora of questions. What other locations contain non-hematopoietic macrophages? Are cardiac macrophages derived from local precursors? How are the various tissue macrophages similar and how are they different? What is the identity of the tissue precursor and how is it maintained throughout adult life? Intense investigation of these questions will no doubt reveal answers in the next few years.

Monocytes are produced in the bone marrow in the steady state from hematopoietic precursors. The most restricted monocyte progenitor known is the macrophage dendritic cell progenitor (MDP), which is developmentally downstream of granulocyte and macrophages progenitors (GMP), and which shares many phenotypic features with the common dendritic cell progenitor (CDP)18, 19. Monocytes produced in the bone marrow enter the blood via CCR220, 21. In the mouse, circulating monocytes are phenotypically and functionally heterogeneous and can be separated according to Ly-6C expression. Between 50-60% of mouse monocytes in the steady state belong to the Ly-6Chigh CCR2high CX3CR1low CD62L+ subset. These inflammatory or classical monocytes have a relatively short circulating life-span and accumulate preferentially in inflammatory sites where they give rise to macrophages. The remaining Ly-6Clow CCR2low CX3CR1high CD62L subset, sometimes referred to as non-classical, patrols the vasculature and accumulates at low numbers in the steady state19, 22. During inflammation, the number of Ly-6Chigh monocytes rises through increased monocytopoiesis in the bone marrow and spleen, contributing to monocytosis9, 10, 23, 24. The function of Ly-6Clow monocytes in tissue, however, requires further study because relatively few Ly-6Clow monocytes accumulate. Evidence shows that monocyte subsets do not arise from separate progenitors, but convert from the Ly-6Chigh to the Ly-6Clow subset25-27. In the human, circulating monocytes can also be separated into subsets based on the expression of CD14 and CD1628. Phenotypic profiling indicates that CD16 CD14+ monocytes, which comprise 80-90% of human monocytes, are similar to Ly-6Chigh monocytes, whereas CD14dim monocytes are most similar to Ly-6Clow monocytes29, 30. A third subset in the human can be identified as CD16+ CD14++ 30, 31. This subset, which circulates at a frequency of 5-7%, was originally called “inflammatory” because it produces TNFα in response to LPS. The relationship between human CD16+ CD14++ monocytes and mouse subsets had been the subject of debate. On the one hand, CD16+ CD14++ cells share many phenotypic features with Ly-6Clow monocytes30. Accordingly, the expression of CD16 is the division line: CD16 monocytes are akin to Ly-6Chigh monocytes whereas CD16+ monocytes are most similar to Ly-6Clow monocytes. The opposing view argues that CD16+ CD14++ cells, which cluster with CD16 CD14++ monocytes, are closely associated with Ly-6Chigh monocytes29. Here, the division line is CD14: CD14++ monocytes resemble Ly-6Chigh monocytes while CD14dim monocytes resemble Ly-6Clow monocytes. Functionally, the patrolling CD14dim and Ly-6Clow monocytes are vascular sentinels. In that respect, they are macrophages of the blood22.

The fate of Ly-6Chigh monocytes upon tissue accumulation has also received attention. A focus of much interest in macrophage biology is the particular function that macrophages acquire upon tissue accumulation. In vitro, macrophages can be generated from bone marrow precursors by various means. Macrophages generated in the presence of IFNg or LPS have been termed M1, or classically-activated, inflammatory, macrophages. Macrophages generated in the presence of IL-4 or IL-10, however, have been called M2, or alternatively activated macrophages, and carry a pro-resolution profile32, 33. Although tissue and inflammatory macrophages likely fall on a continuum that lies between (and outside of) the M1 and M2 definitions, the terminology has nevertheless been helpful in efforts aimed at elucidating macrophage heterogeneity. When Ly-6Chigh monocytes infiltrate atherosclerotic lesions, for example, they differentiate to F4/80+ and Mac3+ macrophages. In lesions, where the inflammatory stimulus is persistent, these Ly-6Chigh monocyte-derived macrophages remain inflammatory by expressing IL-1β and TNFα, and by contributing to oxidative stress9. In this respect, Ly-6Chigh monocyte-derived macrophages are M1 macrophages.

In the context of inflammation resolution, M1 macrophages are replaced by M2 resolution-mediating macrophages. It has been proposed that this occurs through local M1 -> M2 conversion34-36. M2 macrophages could also derive from less inflammatory Ly-6Clow monocytes. Alternatively, M2 macrophages may arise through direct differentiation of Ly-6Chigh monocytes in an microenvironment that favors resolution (Figure 2). This possibility should be explored experimentally as it is enticing for several reasons. First, the macrophage turnover kinetics in the infarcted myocardium are remarkably fast (see below). This suggests that newly recruited cells are continuously replacing “old” cells. Second, recent evidence indicates that Ly-6Clow monocytes function predominantly as vascular sentinels, and infiltrate tissue at very low frequencies. Third, in the steady state, Ly-6Clow monocytes derive from Ly-6Chigh monocytes, and it is not clear if the conversion path involves intermediate stages, i.e. Ly-6Chigh monocyte -> Ly-6Clow monocyte -> M2 macrophage. Sophisticated lineage-tracing studies are therefore required to elucidate monocyte/macrophage lineage relationships during resolution of inflammation, in the ischemic myocardium, testing the hypothetical options outlined in Figure 2.

Figure 2
Potential lineage relationships of monocytes and macrophages after myocardial infarction. In steady state, monocyte conversion from Ly-6Chigh to Ly-6Clow may occur in blood and bone marrow27. It is generally accepted that Ly-6Chigh monocytes give rise ...

Infarct healing

The typical trigger of myocardial infarction is plaque rupture in a coronary artery, which suddenly stops the arterial blood flow feeding downstream organ areas. Deprived of oxygen, the non-perfused myocardial tissue undergoes necrosis. Accumulation of leukocytes in the first minutes to hours after MI was recently imaged with intravital microscopy for the first time37, 38. Surprisingly, monocyte recruitment may outpace neutrophils shortly after coronary ligation38. Nevertheless, neutrophils are the first leukocyte population to reach a robust peak of several hundred thousand cells within the first day after onset of ischemia3. The short-lived cells are recruited through adhesion molecules such as E-and P-Selectin and ICAM-1, and the chemokine IL-839. Neutrophil’s presence is generally seen as detrimental, as they contribute to the damage inflicted by reperfusion injury. Their main function is to defend the organism against invaders such as microbes. To fulfill this task, they carry an armamentarium of inflammatory cytokines, are phagocytic, and impose oxidative stress on the tissue in which they accumulate. Their presence in the healing infarct wanes quickly, but they may linger longer if inflammation does not resolve. Some of these cells can be found in the cardiac wound as late as 7 days after MI.

The next major cell classes dominating the infarct are monocytes and macrophages. These myeloid cells can be found in high numbers, up to a million cells, in the infarct. An inflammatory phenotype (Ly-6Chigh monocytes/M1-type macrophages) dominates initially and is followed by cells with a lesser inflammatory phenotype promoting tissue repair (Ly-6Cint/low monocytes/M2-type macrophages). These cells are discussed in more detail in the following paragraphs.

Other leukocytes invading the infarct include dendritic cells40, lymphocytes41, 42, and mast cells43. Compared to neutrophils, monocytes and macrophages, their numbers are lower. However, they may have an important role in regulating infarct healing and the myeloid cell response.

When the inflammatory activity resolves, non-leukocyte cells join the rebuilding activities in the infarct. Solicited by angiogenic factors such as VEGF, numerous vessels sprout into newly forming granulation tissue. These small capillaries can appear as early as a few days after injury but their highest numbers are found weeks later. In non-reperfused infarcts, the highest density of neovessels is observed in the border zone, i.e. next to non-infarcted tissue. Initially, new vessels only consist of endothelial cells, but acquire a more mature morphology, including a pericyte coat, over time44.

Myofibroblasts produce collagen, the extracellular matrix that strengthens the emerging infarct scar. Impaired collagen deposition or accelerated degradation of collagen due to high matrix metalloproteinase activity45 can lead to infarct rupture and sudden death. Infarct expansion is a less drastic but still detrimental phenotype of insufficient matrix generation46. Hence, collagen-producing cells play a major role in later wound healing stages. Because parabosis studies linking wild type mice after coronary ligation with GFP+ mice have argued that circulating progenitors only give rise to leukocytes in the infarct47, α-smooth muscle actin positive cells may derive from local progenitors, for instance the very numerous resident cardiac fibroblasts.

Monocytes in the infarct

Monocytes are among the very first cells recruited to ischemic myocardium. Intravital microscopy of the beating mouse heart37, 38 allows to follow leukocyte action in the ischemic heart with high temporal and spatial resolution in vivo. Monocyte recruitment outpaced neutrophils within the first 30 minutes after the onset of ischemia (Figure 1)38. It is currently not clear which monocyte subset is recruited during the first minutes after MI, and what the function of these cells entails. However, one could hypothesize that these are patrolling Ly-6Clow monocytes that amplify the initial inflammatory signal. Discriminating monocyte subsets by imaging will contribute to a better understanding of their phenotype, source and function.

Figure 1
Intravital microscopy of monocyte and neutrophil recruitment in the first 30 minutes after myocardial infarction in GFP reporter mice. Dedicated image stabilization and motion compensation techniques allowed to follow this process in vivo. Interestingly, ...

Two sequential phases defined by the expression of Ly-6C on monocytes/macrophages can be identified in the infarcted myocardium3. The inflammatory Ly-6Chigh monocyte subset is recruited during the first days after MI, via the chemokine MCP-148. Days later, when inflammation resolves in the cardiac wound, the presence of these inflammatory cells wanes. Starting around day 4 after MI, the infarct tissue accumulates Ly-6Cint/low monocytes/macrophages. (Figure 2). On day 7, Ly-6Cint/low F4/80high cells outnumber Ly-6Chigh cells in the heart3. Similar monocyte kinetics can be observed in the blood of mice after coronary ligation3 and in patients with acute MI49. This time course corresponds to expression of M1-type markers in the tissue early after injury, and M2-type macrophage markers later50.

Interestingly, the turnover of myeloid cells in the infarct is very rapid. Even days after injury, monocytes are recruited at a rather high rate and reside only for an average of 20 hours in the cardiac wound10. Thereafter, most of them become apoptotic. While only between 5 and 13% of the entire accumulating CD11b+ leukocyte population exits the infarct within 24 hours, some of these cells accumulate in the liver, lymph nodes and the spleen10. It is currently unknown if cells that exit the site of inflammation do so actively, and whether they merely perish elsewhere. Alternatively they may carry a specific function, for instance transmitting information to sites of monocyte production.

Within the first week of injury, the function of myeloid cells changes over time. During day 1-4 after ischemia, the milieu is highly inflammatory. Ly-6Chigh monocytes have a high payload of inflammatory cytokines such as TNFα and proteases3. Together with inflammatory macrophages, they form a ‘demolition crew’ which digests dead cells and extracellular matrix. These cells clear the infarct of debris by phagocytosis, a prerequisite for replacing the injured tissue with granulation tissue and the evolving scar. An unresolved question is whether this debris is removed from the heart to distant organs or recycled onsite. During the following rebuilding phase, the inflammatory activity resolves and gives way to Ly-6Cint/low monocytes/macrophages. These cells carry a lower content of inflammatory molecules and proteases. Instead, they release VEGF and TGFβ, supporting angiogenesis and collagen production. Both healing phases are required for sufficient wound healing. If either is ablated, the scar-building process is disturbed3.

Monocytes and macrophages may influence tissue regeneration in yet to be discovered ways. Work on the hematopoietic stem cell niche illustrates that macrophages can have close relationships with multipotent progenitor cells51, 52. Recent insight highlights their role in regulating production of red blood cells53. These regulatory macrophage actions are based on cross talk with hematopoietic stem cells in the bone marrow. It is tempting to speculate that macrophages could act similarly in other tissues, for instance by interacting with cells that have regenerative capacities in the injured heart. Specifically, macrophage subsets may differentially influence activity of proliferating endothelial cells, fibroblasts, endogenous cardiac progenitors, or stem cells that were transferred into the heart with the intention to rebuild myocardium after MI. The latter point may guide timing of cell therapy, as an inflammatory milieu provided by M1 macrophages could hinder survival, differentiation, and integration of therapeutically transferred cells.

It is currently unclear how monocytes and macrophages share the burden of work, also due to the difficulties when trying to clearly separate the cell populations using surface markers. Advanced flow cytometry gating strategies, new surface markers12, together with a higher number of channels available in current flow cytometers, enables better discrimination between tissue monocytes and macrophages. Potential lineage relationships in the infarct are discussed below.

Lineage relationships in the infarct

Although evidence for lineage relationship in the infarcted myocardium is rather sparse, there is considerable evidence in other tissues as to how monocyte subsets and macrophages correspond to each other developmentally. The emerging picture is as follows: In the steady state, the tissue is populated by resident macrophages, many of which do not rely on the bone marrow for replenishment but self renew from local progenitors or through proliferation16. This has not yet been explored specifically for macrophages in the heart. Shortly after injury, Ly-6Chigh monocytes infiltrate the infarct in large numbers3. Many of these monocytes may not differentiate to macrophages but either exit or die in tissue. Those that differentiate acquire M1-like properties, continue to express Ly-6C, and contribute to inflammation (Figure 2). Over time, as inflammation gives way to resolution, a second Ly-6Cint/low phase emerges. We will have to address experimentally whether macrophages dominating this regenerative wound healing phase arise via the differentiation of Ly-6Chigh monocytes (Figure 2), and less via differentiation of Ly-6Clow monocytes or local M1 -> M2 macrophage conversion. Over time, as inflammation completely subsides, a population of F4/80high macrophages resembling steady-state macrophages returns. Future studies will determine whether these macrophages derived from a circulating or local precursor.

Sources of monocytes after MI

The bone marrow is the primary site of production for blood cells. The production of leukocytes is tightly regulated by a team of house keeping cells forming the hematopoietic niche. Key constituents include CD169+ macrophages, mesenchymal stem cells, osteoblasts and endothelial cells. These niche cells organize HSC retention and provide signals that regulate proliferation or quiescence of HSCs via adhesion molecules (e.g. selectins) and soluble cytokines (e.g. CXCL12, SCF)51, 52. Release of monocytes from the bone marrow into the blood stream depends on the chemokine receptor CCR220 which also regulates recruitment to the site of inflammation48. The infarct recruits these cells from the blood stream.

Within the first 24 hours after coronary ligation in mice, roughly half of all monocytes recruited to the heart derive from a splenic reservoir11. Reservoir monocytes reside in the subcapsular red pulp of the spleen and resemble closely their circulating counterparts, which they outnumber significantly. Upon myocardial infarction, splenic monocytes increase motility, at least partially, by signaling of angiotensin-2 through the angiotensin-2 subtype 1 receptor expressed on their cell surface11, 54. The cells then intravasate into splenic veins and leave the organ (Figure 3), to accumulate at inflammatory sites. In mice, this leads to a drastic shrinkage of the spleen within the first 24 hours after MI. The organ weight declines by ~50%, and so does the number of splenic monocytes. The bone marrow and blood pool also substantially contribute to the monocytes recruited to the infarct.

Figure 3
Intravital microscopy of the spleen in a CX3CR1GFP/+ mouse shortly after myocardial infarction shows intravasation and departure of a splenic monocyte. Adapted from reference11.

Since the residence time of monocytes and macrophages is short, and recruitment to the infarct continues at levels of several hundred thousand cells per day, the production of these cells intensifies to meet the high demand after the reservoirs exhaust. We55 and others56 observed that myocardial infarction increases the activity of the hematopoietic system. In humans, increased bone marrow uptake of the PET tracer 18F-FDG, a radiolabeled glucose analog, indicates a higher metabolic activity56. The human bone marrow releases hematopoietic progenitors after myocardial infarction57. In mice after coronary ligation, these cells home for the spleen, where they seed the organ depending on VLA-4 and SCF to initiate extramedullary hematopoiesis55. This monocyte production is stimulated by signaling through the IL-1 receptor, replenishes the splenic reservoir by day 6 after MI, and continues to supply the infarct with a significant number of cells (~50% of infarct monocytes in mice derive from the spleen on day 6 after coronary ligation)10.

Sympathetic nervous signaling is a trigger of bone marrow stem cell release after MI. Treatment with a β3 specific adrenoreceptor inhibited the release of HSCs into the blood55. These findings raise the question whether β-blockers in clinical use with affinity to the β3 receptor subtype inhibit HSC release in patients after myocardial infarction, and perhaps have an anti-inflammatory effect by reducing extramedullary production of inflammatory leukocytes.

Monocytes and macrophages in normal and failing myocardium

Macrophages reside in many normal tissues during steady state. The heart is no exception2, 3. Improved detection strategies, including fluorescent reporter genes, visualize these cells nestled within the normal myocardium in direct contact with endothelial cells and myocytes2. During steady state, their gene expression profile resembles noninflammatory M2 macrophages2. The number of extravasated monocytes in the healthy heart is low. However, monocytes can be found patrolling the myocardial vasculature38. The patrolling behavior was previously described for Ly-6Clow monocytes in other tissues22, 58. The precise function of patrolling monocytes and tissue macrophages in the heart is currently unclear.

What is the role of myocardial monocytes and macrophages in disease, i.e. in the failing heart? Their increased presence in the myocardium has recently been described in mice with heart failure due to pressure overload59 and in the remote zone after myocardial infarction in mice and patients (Figure 4)60, 61. It is well known that myocyte hypertrophy, myocyte death, changes in the balance of extracellular matrix production, and protease activity are central in the evolution of heart failure, but the role of monocytes and macrophages within this system is not well understood. Specifically, we lack knowledge about their origin, phenotype and function in failing hearts. Leukocyte numbers in the remote myocardial tissue are orders of magnitude lower compared to the acutely ischemic infarct. Nevertheless, one interesting hypothesis is that monocytes and macrophages may instruct and interact with parenchymal cells in the myocardium (Figure 4). Macrophages’ importance in many other diseases is well recognized62, 63. For instance, myeloid cells digest extracellular matrix and promote tissue destruction in atherosclerosis4, 64, 65 and rheumatoid arthritis66, 67, and they instigate fibrosis in liver disease68. Hence, it is conceivable that these cells have an active role in the evolution of heart failure by supplying pro-fibrotic signals, or enhancing protease activity and ventricular dilation. Inflammatory macrophages may even accelerate myocyte apoptosis in failing hearts. Alternatively, these cells may be innocent bystanders or merely dispose of apoptotic myocytes. Clinical signs of inflammation in heart failure patients, such as increased CRP, high cytokine levels69, 70, and the predictive value of the white blood count71, 72 underscore the likelihood of an inflammatory component in left ventricular remodeling. Future research should address the mode of recruitment, if there is local macrophage proliferation in the failing heart, the function of leukocytes in the remote myocardium, and their interaction with endothelial cells, myocytes, and fibroblasts (Figure 4).

Figure 4
Open questions about the phenotype, behavior and function of monocytes and macrophages in the remote zone after myocardial infarction. The lower right inset shows immunoreactive staining for CD68+ macrophages in the remote zone of a patient who died shortly ...

Cross talk between organ systems

The heart is intimately linked to all organ systems. On the obvious side, it supplies the entire body with oxygenated blood. A decline of this function compromises the function of other organs, possibly enhancing heart failure in a vicious cycle. Renal function is a prominent example, as decreased perfusion of the kidneys causes fluid retention and increases stress on the heart due to loading conditions. Similar connections may exist between the cardiovascular and the metabolic, endocrine, immune and hematopoietic systems, and these interactions may enhance heart failure.

Monocytes and macrophages closely link atherosclerosis and myocardial infarction with the immune and hematopoietic system. Derailed defense functions of macrophages, which fail to remove lipid deposits from the diseased arterial wall, lead to inflammatory complication of atherosclerotic plaque. Aberrant cholesterol handling enhances the production of leukocytes in the bone marrow73, and, at least in mice, initiate extramedullary myelopoiesis in the spleen9, 74. In human patients, increased activity of macrophages gives rise to vulnerable plaques, plaque rupture, and myocardial infarction. Thus, myocardial infarction occurs in a setting of chronic inflammation, with an elevated activity of the hematopoietic and immune system. The increased availability of inflammatory leukocytes due to preexisting atherosclerosis changes the inflammatory response to acute infarction and modulates myocardial healing. In ApoE-/- mice with atherosclerosis, inflammatory leukocytes are recruited for a longer time and in higher numbers to the cardiac wound, disturbing the resolution of inflammation in the heart and enhancing post MI remodeling75.

There is another perspective to this interaction of chronic inflammation in the artery wall and acute inflammation in the infarct. We have long known that the first year after an ischemic event is particularly dangerous, and that many patients develop re-infarction76, 77. A systemic flare-up of inflammation in the vessel wall after MI may cause these secondary ischemic events78. Increased activity of the sympathetic nervous system translocates leukocyte progenitors to the spleen and accelerates overall production of inflammatory leukocytes55. These cells are then not only available for recruitment to the infarct but may also increase inflammatory activity in atherosclerotic plaque. Hence, it seems reasonable to target the nervous, immune or hematopoietic systems to either prevent re-infarction or ameliorate the evolution of post-MI heart failure. This concept is already implemented to some degree, i.e. by using beta blockers, lowering blood cholesterol levels, controlling obesity, and treating diabetes. However, current clinical therapeutics do not specifically target inflammatory feed back loops.

Tools to study monocytes and macrophages in the heart

While the first histochemical studies reported on leukocyte and macrophage presence in acute infarcts79, a number of newer tools enabled analysis of leukocyte subsets, increased sensitivity, resulted in quantitative data and facilitated in vivo measurements. Flow cytometric analysis of digested infarcts was a major advance, as this approach enumerates the total cell number per unit of tissue. Multichannel capabilities allow staining for surface marker combinations, and hence the identification and isolation of monocyte subsets. The use of CX3CR1GFP reporter mice improved the sensitivity of ex vivo histology2, 61. In vivo microscopy of monocytes reported on the cell’s distinct migration paths and patterns. For instance, it revealed the increased motility of splenic monocytes after MI (Figure 3). Imaging the heart with microscopic resolution has only recently been established (Figure 1), as the cardiac and respiratory motion represent major hurdles. These were overcome by using tissue stabilization in conjunction with ECG and respiratory triggering of image acquisition37, 38. Organ-level imaging modalities, including magnetic resonance imaging80, PET61, fluorescence molecular tomography81 and hybrid approaches82 can now follow monocyte and macrophages and their molecular function in murine infarcts non-invasively (Figure 5). Non-invasive leukocyte imaging answered questions regarding how monocyte and macrophage content in the infarct influences left ventricular remodeling and the evolution of heart failure. Monocyte and macrophage imaging may rely on nanoparticles that are taken up by these cells and that can be detected non-invasively. These include PET isotope labeled nanoparticles83, fluorochrome labeled nanoparticles81, gadolinium-84 or fluorine-1985 labeled liposomes, and iron oxide nanoparticles that are detectable with T2* weighted MR imaging80. First pioneered for this application in the mouse80, iron oxide nanoparticles were recently used in 2 clinical trials focussing on macrophages in acute infarcts86, 87. These imaging tools will likely enable clinical studies that aim to translate basic findings and will follow emerging therapeutics that target monocyte and macrophage biology.

Figure 5
Noninvasive imaging of monocytes and macrophages. Left upper panel: hybrid fluorescence molecular tomography / Xray computed tomography imaging of protease activity in an ApoE-/- mice after coronary ligation (adapted from reference75). Right upper panel: ...

Clinical translatability

What is the evidence that discoveries in the mouse translate to patients with myocardial infarction? A large number of clinical studies support concepts of cardiac monocyte and macrophage heterogeneity recently described in mice. Studies have shown, for example, that CD14++CD16+ monocytes predict for cardiovascular events88-90. However, seemingly conflicting data91, as well as lack of consensus as to how human and mouse subsets correspond, impede translation of mechanistic insights. While tissue data in the heart are still lacking, a two-phased monocyte response has been observed in the blood of patients after myocardial infarction49. Inflammatory CD14+CD16- monocytes peaked on day 3, whereas CD14+CD16+ monocytes peaked on day 5 after MI, recapitulating the temporal pattern observed for Ly-6Chigh and Ly-6Clow monocytes in mice3. Patients with a higher blood level of inflammatory monocytes had worse myocardial salvage and lower ejection fraction 6 months after MI, measured by MRI49. This intriguing study does not yet answer the question of causality in patients. Possibly, an increased inflammatory activity leads to worse healing and outcome. Alternatively, a more extensive injury may have caused higher blood monocyte levels and lower ejection fraction 6 months later. A number of clinical studies confirm the correlation of blood leukocyte levels in heart failure with prognosis71, 72.

Although many open questions persist, there are also some intriguing clues on the response of the hematopoietic system in patients after MI. An increased level of hematopoietic progenitors was found in the blood57, and the metabolic activity of the bone marrow increased56. There is also evidence for an increased progenitor activity in the spleen of patients after MI55. Future studies will show if there is splenic monocyte release in patients with MI, and if biphasic monocyte recruitment can be observed in infarct tissue.

The presence of macrophages in the remote myocardium after MI has been confirmed in patients by histology61 and in a macrophage imaging study56. However, their function remains to be elucidated.

Open questions

We are beginning to better understand the role of monocytes, macrophages and their subsets in the heart, but there are more questions than answers. The role of these cells in the healthy heart is unclear. After MI, we do not yet understand what signals initiate the resolution of inflammation in the cardiac wound. Newer microscopic imaging techniques may soon elucidate better how monocytes are recruited to the injured heart, especially when the endothelium is disrupted. We have never seen a monocyte or macrophage move from the border zone into the core of an infarct, although we have found these cells there. What are their migration patterns, how do the cells move, and how fast?

The high turn over of leukocytes in the infarct obviates the importance of leukocyte supply and production. Only very few studies have investigated how the hematopoietic system, including the bone marrow, reacts to myocardial infarction. Given the distance of organs such as the spleen and the bone marrow from the heart, it would be interesting, also as a possible way of interacting therapeutically with the inflammatory response, to learn more about the signals that regulate monocyte supply. What are the danger signals that report cardiac injury to other organ systems, including the spleen and the bone marrow?

While macrophages are present in the remote zone after myocardial infarction and in mice with pressure overload, it is unclear if they are important and what functions they pursue. Finally, from a perspective of monocyte and macrophage heterogeneity, precise lineage relationships between these cells and their subsets have yet to be determined in the steady state as well as in the diseased heart.

Conclusion

The motivation behind the questions above is the need for new treatment concepts in heart failure. We should also explore how our current therapeutics interfere with monocyte and macrophage function. For example, monocyte progenitor release from the bone marrow after coronary ligation in mice depends on β-adrenergic signaling. Further, ACE inhibition decreases monocyte and macrophage numbers in the infarct of mice by inhibiting the mobilization of splenic monocytes. Are similar mechanisms active in patients?

Newer therapeutic avenues may target the inflammatory activity after MI directly. There are two major clinical atherosclerosis trials under way, exploring the role of the anti-proliferative drug methotrexate92 and the action of neutralizing interleukin-1β93, a cytokine that likely supports post-MI monocyte production in the spleen10. These trials may provide important cues towards the role of monocyte and macrophage activity in patients.

Finally, understanding the signaling pathways and the fate of monocytes and their progenitors after MI will support the search for specific therapies. One example is RNAi silencing of the chemokine receptor CCR2, which inhibits the recruitment of inflammatory monocyte subset in mice with MI82, 94, possibly sparing non-inflammatory monocyte and macrophage subsets. Any potential immune-targeted therapy will face scrutiny regarding unwanted effects. However, targeting a culprit subset, motivated by increased knowledge on monocyte and macrophage heterogeneity, may spare important immune functions such as repair and defense against infection.

Acknowledgments

Figures were produced using Servier Medical Art.

Sources of funding

This work has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (R01HL095612, R01HL095629, R01HL096576, Contract No. HHSN268201000044C).

Nonstandard Abbreviations and Acronyms

CDP
common dendritic cell progenitor
CLIO
cross-linked iron oxide nanoparticles
FDG
fluorodeoxyglucose
GMP
granulocyte and macrophage progenitor
GFP
green fluorescent protein
HSC
hematopoietic stem cells
LPS
lipopolysaccharide
MDP
macrophage dendritic cell progenitor
MRI
magnetic resonace imaging
PET
positron emission tomography

Footnotes

Disclosures

None.

References

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