Macrophages in Ischemic Heart Failure: Yesterday, Today, and Tomorrow : Cardiology Discovery

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Macrophages in Ischemic Heart Failure: Yesterday, Today, and Tomorrow

Liu, Demin1; Yan, Wenjun2; Huang, Jingwen3; Zhao, Jianli3; Kilby, Houston3; Christopher, Theodore A.3; Lopez, Bernard3; Tao, Ling2; Ma, Xinliang3; Gu, Guoqiang1,∗; Wang, Yajing3,∗

Editor(s): Xu, Tianyu; Fu., Xiaoxia

Author Information
Cardiology Discovery 1(2):p 128-134, June 2021. | DOI: 10.1097/CD9.0000000000000010
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Abstract

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality.[1] Myocardial infarction (MI) is now recognized as a syndrome where ischemia causes myocardial cell injury and death. MI increases cardiovascular mortality and can lead to cardiac arrhythmia, increased incidence of heart failure (HF), and cardiac death.[2,3] Nearly 70% of all HF syndromes can be attributed to underlying IHD.[4] Prolonged ischemia can lead to irreversible cell death that decreases the global function of the heart. Over time, the damaged myocardium is replaced with a non-contractile scar, contributing to left ventricle dysfunction and often leading to the development of HF with reduced ejection fraction. Despite efforts to address the key prevention risk factors for IHD, the incidence of HF hospitalizations remains high and is projected to rise.[5]

The death of cardiomyocytes and other cardiac cells after MI is the proximal cause of cardiac dysfunction. Currently, for acute MI patients, timely reperfusion therapy with primary percutaneous coronary intervention or thrombolytic therapy effectively limits the extent of infarction. Reperfusion therapy offers improved survival and quality of life.[6,7] However, therapeutic manipulation of the ensuing repair process, which is driven principally by robust tissue inflammation and subsequently by its active suppression and resolution, is largely absent.[8] To develop new therapeutic options for patients with IHD, we must understand the cellular and molecular mechanisms of cardiac injury and repair so that they can be manipulated.

Yesterday: inflammation in post-MI cardiac repair and traditional view of macrophages in ischemic heart injury

More than 70 years ago, cardiac pathologists noted that MI triggers an intense inflammatory reaction characterized by infiltration of leukocytes into the infarcted heart. Since then, recognition of the injurious properties of leukocytes and their close association with cardiomyocytes in the viable border zone of an infarct suggests that subpopulations of blood-derived cells can adhere to viable cardiomyocytes and might exert cytotoxic effects extending ischemic injury.

MI is a key trigger in activating the acute inflammatory responses. Cardiac repair after MI includes an inflammatory phase followed by a reparative/proliferative phase. After the ischemic injury, the dead cardiac tissue rapidly activates innate immune pathways that trigger an intense inflammatory reaction. Local mast cells, cardiac resident macrophages, and damaged endothelial cells[9,10] begin to produce pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-1β, IL-6.[11,12] The chemoattractant CC-chemokine ligand 2 (CCL2) and CCL7 mobilizes neutrophils and monocytes from the blood pool that accumulate in the myocardium and participate in local inflammation.[13] Neutrophils appear in injured cardiac tissue spots in as early as 30 minutes, decrease in number at 3 days, and almost entirely disappear at 7 days.[14] Monocytes continue to accumulate in the ischemic heart and differentiate into macrophages for several days. During this time, the inflammatory reaction resolves and clears the necrotic cells and infarction debris, preparing the infarct for the proliferative phase of healing characterized by the disappearance of neutrophils and the polarization of macrophage subpopulations. Additionally, there is a decrease of pro-inflammatory cytokines and chemokines.[15] After several weeks, the inflammation and reparation coordinated by mast cells, neutrophils, monocytes, and macrophages subsides. The damaged myocardial tissue then moves to the maturation and scar formation process.[16]

It is generally believed that the immune system plays an essential role in cardiac repair that involves both the innate and adaptive immune systems. The degree of inflammation is a major determinant of the extent of MI and subsequent cardiac remodeling and function. The dynamic changes in leukocyte subsets in the ischemic myocardium are time-dependent and site-specific [Figure 1]. These alterations in inflammatory patterns have either protective or detrimental effects on cardiac function during chronic ischemia. Early inflammatory activation is a necessary event for the transition to later reparative and proliferative processes. Appropriate and timely containment and resolution of inflammation are further determinants of the quality of wound healing. A prolonged inflammatory response leads to sustained tissue damage and improper healing, thereby promoting infarct expansion, adverse remodeling, and chamber dilatation.[8]

F1
Figure 1:
Dynamic changes in leukocyte subsets in post-myocardial infarction (MI) cardiac repair. The early inflammatory activation after MI is characterized by robust innate and adaptive immune cell infiltration and tissue digestion. In this phase, monocyte is polarized toward a pro-inflammatory macrophage. This is subsequently followed by a phase of resolution and wound repair, during which the monocyte is polarized toward an anti-inflammatory state. After healing, larger infarcts will exhibit a state characterized by chronic inflammation, leading to progressive ventricular dilatation and heart failure. CCR2: C-C chemokine receptor type 2.

In light of increasing evidence that inflammation plays roles in the progression of HF, the Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy (ACCLAIM) study investigated the effect of non-specific immunomodulation on the HF process and prognosis in this group of patients. In this study, a blood sample collected from the patient was treated externally with a gaseous mixture of oxygen and ozone. This blood sample was then administered back to the patient in the form of an intragluteal injection to induce a beneficial immune system response. In this study, no significant reduction in cardiovascular mortality or hospitalization due to HF was achieved.[17] In another large clinical trial, pexelizumab (a humanized monoclonal antibody that binds the C5 component of complement) did not reduce mortality and major adverse events in patients with ST-segment-elevation MI.[18] Unfortunately, in those clinical trials evaluating these “anti-inflammatory” therapies, no beneficial effects were found in HF patients. On the other hand, there is a consensus that these studies should be continued.[19]

The heart is a complex multicellular organ comprised of a range of distinct cell-types. Cardiomyocytes constitute approximately one-third of resident cardiac cells; the remaining two-thirds are referred to as non-cardiomyocytes and include fibroblasts, smooth muscle cells, endothelial cells, autonomic motor neurons, immune cells, mast cells, and macrophages. While cardiomyocytes possess inherent conduction capabilities that mediate the characteristic contractile forces of the heart, non-cardiomyocytes are responsible for matrix deposition, vascularization, and autonomic regulation. Cardiomyocytes and non-cardiomyocytes communicate via biochemical signaling through cytokine and growth factor secretion.[20]

Monocyte/macrophages contribute centrally to wound healing. Monocyte recruitment has been observed in various forms of tissue injury and represents a hallmark characteristic of both infectious and sterile inflammation.[21] Immature cells in the bone marrow are thought to give rise to circulating monocytes that continuously migrate to peripheral tissues.[22] In MI, circulating blood monocytes migrate into the infarcted heart and differentiate into macrophages. Macrophages are a heterogeneous group that can promote both injury and repair after MI. Macrophages impact various wound healing processes, including the activation of fibroblasts and endothelial cells, with the former vital for scar tissue formation and the latter important for angiogenesis.[23] In macrophage-deficient mice, myocardial infarct healing is impaired, and myocardial scar rupture occurs.[24,25] However, excessive numerical expansion of macrophages also limits cardiac repair through excessive inflammatory tissue damage.[26] The discriminating functions of macrophages within heterogeneous populations remain unclear and challenging.

Traditionally, macrophages are thought to be polarized with opposing M1 lymphocyte antigen 6C (Ly6Chigh), and M2 (Ly6Clow) subtypes present following tissue injury. M1 macrophages are described as being “classically” activated. M1 activation of macrophages can be initiated by the recognition of pathogen-associated molecular patterns like lipopolysaccharide, chitin, and other intracellular pathogens. The inflammatory function of this pathway in M1 macrophages is essential to innate immunity in response to pathogenic stimuli. M1 macrophages also encourage the differentiation of inflammatory T-cell phenotypes, which further participate in mediating inflammation.[27] Interferon (IFN)-γ is also known to promote M1 activation. It is a potent microbicidal, cytotoxic effector that is transiently produced by natural-killer (NK) cells, with sustained production by Th-1 cells. During the innate immune response, classically-activated macrophages produce pro-inflammatory cytokines, which play a key role in host defense. However, prolonged exposure to such compounds can result in extensive damage to the host, as is seen in many inflammatory diseases.[28] Pro-inflammatory M1 macrophages are predominant at day one to three post-MI, which is associated with excessive inflammation and ischemic injury.

In contrast, “alternatively-activated” macrophages (M2) are activated when they are exposed to anti-inflammatory cytokines, such as IL-4, IL-10, and IL-13.[29] Distinct from those “classically” activated, M2 macrophages exhibit a growing spectrum of phenotypic and functional varieties. They can be induced by different stimuli and accordingly have specific classifications denoted by their stimulus and effector functions. The reparative M2 macrophages represent the predominant macrophage subset 5 days after MI. M2 macrophages have both proliferative and wound healing properties, and promote collagen synthesis, fibrosis, and other tissue remodeling functions.[30] They also demonstrate anti-inflammatory actions by producing anti-inflammatory cytokines and chemokines, such as IL-10 and CCL17.[31] Finally, M2 macrophages release vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β, supporting angiogenesis and collagen production.[32,33] Appropriate and timely switch of inflammatory macrophages to a reparative phenotype limits inflammation and contributes to optimal healing post-MI.[8]

Today: novel subgroups of macrophages in ischemic heart injury and different roles of cardiac resident macrophages versus infiltrated monocytes derived macrophages

Over the past 40 years, the prevailing view has been that tissue macrophages originate from circulating blood monocytes. Recently, a growing body of evidence has challenged this dogma and revolutionized our understanding of macrophage heterogeneity and origin.[34] Each tissue has its own composition of embryonically derived and adult-derived macrophages. Many tissue-resident adult macrophages are established embryonically and persist separately from the blood monocyte pool.[35] In the mouse, cardiac resident macrophages first enter the heart tissue during embryonic development and persist into adulthood independent of monocyte recruitment. Macrophages constitute 7% to 8% of non-cardiomyocytes in the murine heart.[36,37]

Gene mapping of cardiac resident macrophages reveals 2 distinct lineages arising at the embryonic and post-natal stages. The earliest cardiac resident macrophages are derived from an erythro-myeloid progenitor in the yolk sac. Postnatally, monocyte-derived macrophages can also migrate to the myocardium to become tissue-resident macrophages. These embryonic and post-natal resident cells can be distinguished from one another based on the expression of C-C chemokine receptor type 2 (CCR2).[38] CCR2+ macrophages are a minority group of cardiac resident macrophages. They are derived from and maintained by the influx of blood monocytes.[38,39] Cardiac resident macrophages that express low CCR2 and Ly6C expression can further be divided into CCR2-Ly6ClowMHCIIlow and CCR2-Ly6ClowMHCIIhigh subgroups.[39] In the steady-state, these two are the majority macrophage subsets present in cardiac tissue. Detailed fate-mapping studies have shown that CCR2-MHCIIlowCX3CR1high cardiac macrophages are derived from embryonic progenitors (yolk sac) before the start of definitive hematopoiesis and populate the heart during embryogenesis.[38] These cardiac-resident macrophages are maintained independently from monocyte-derived macrophages and replicate locally within the heart.[40] They have minimal inflammatory potential but maintain vascular integrity.[38,41]

With a different embryologic origin compared to monocytes, cardiac-resident macrophages replicate using their own source. Using a combination of cell tracking, fate mapping, parabiosis, and single-cell transcriptomic, one study has demonstrated that healthy murine myocardium has 4 transcriptionally distinct cardiac macrophages.[42] TIMD4 (T cell immunoglobulin and mucin domain containing 4)-LYVE1(Lymphatic vessel endothelial hyaluronan receptor 1)-MHCIIlowCCR2 resident cardiac macrophages self-renew with minimal blood monocyte input, while a subset of TIMD4-LYVE1-MHCIIhighCCR2 macrophages are partially replaced by monocytes. Two subsets of TIMD4-LYVE1-MHCIIhighCCR2+ macrophages are fully replaced by monocytes.[42] Resident monocytes function in a hierarchy distinct from monocytes. Following MI, resident macrophages decrease to only 2% to 5% of the total cardiac macrophages in the injured zone, which is replenished by macrophages from blood monocytes.[40] However, resident macrophage depletion impairs cardiac function and infarct healing, which cannot be compensated by recruited macrophages.[42]

Resident macrophages are implicated in the post-MI remodeling process. Following acute MI, cardiac cell necrosis and apoptosis (crucial components of ventricular remodeling in the acute inflammatory phase) need to be addressed appropriately to improve tissue healing and functionally recovery.[43,44] Studies have shown that efferocytosis (phagocytosis of apoptotic cells) via the macrophage receptor myeloid-epithelial reproductive tyrosine kinase (MerTK) is a significant contributor to cardiac repair and remodeling after experimental MI.[45,46] MerTK deficiency has been shown to decrease the ability of macrophages to recognize necrotic cells, increase the accumulation of apoptotic cardiomyocytes, and compromise the systolic performance of the infarcted heart.[45] One study suggested that MerTK- and Mfge8-dependent clearance of dying cardiac cells following MI by tissue monocytes/macrophages plays a critical role in the fine-tuning of the reparative process after ischemic cardiac injury.[47] DeBerge et al[48] demonstrated that resident cardiac MHCIIlowCCR2 macrophages participate in the MerTK-dependent phagocytosis and cardiac wound debridement after reperfusion. In a reperfused murine heart, MerTK is hampered by reperfusion-induced MerTK cleavage. The potential mechanism of MerTK cleavage on CCR2 resident cardiac macrophages is triggered by CCR2 dependent recruitment of blood Ly6Chigh monocytes.[15] CCR2 blockage maintained surface MerTK on CCR2 cardiac resident macrophages, which secreted pro-reparative cytokines, including TGF-β; deficiencies of MerTK reduced IL-10 and TGF-β production.

Cardiac CCR2+ macrophages, on the other hand, are essential upstream mediators of the inflammatory response to myocardial injury. One study using different mouse models of cardiac tissue damage (acute MI or reperfused myocardial injury) demonstrates that there is a shift in macrophage populations where CCR2 tissue-resident macrophages are predominantly replaced by CCR2+ monocyte-derived macrophages and infiltrating monocytes.[49] Using a syngeneic cardiac transplantation model of ischemia-perfusion injury in combination with intravital 2-photon microscopy, Bajpai et al[49] demonstrated that resident CCR2+ macrophages promote monocytes recruitment and infiltration through a myeloid differentiation primary response 88-dependent mechanism that results in inflammatory chemokines and pro-inflammatory cytokine release. Cardiac resident CCR2+ macrophages also produce chemoattractants C-X-C motif chemokine ligand (CXCL)2 and CXCL5 to attract neutrophils to the site of ischemic myocardial tissue to promote the extravasation of neutrophils.[50]

Tomorrow: immunoregulation as a potential therapeutic intervention against ischemic heart failure

Based on the current understanding of macrophage polarization, some strategies have been developed to explore the possibility of enhancing post-MI cardiac repair by modulating protective/harmful macrophage subpopulations. Fan et al[51] demonstrated that macrophage-expressed Dectin-1 plays a pathogenic role during myocardial ischemia reperfusion (IR) injury by promoting macrophage polarization toward the M1 phenotype and neutrophil infiltration. Dectin-1 knockout or inhibition (anti-Dectin-1 antibody) ameliorate IR injury. The same group recently reported that macrophage-specific Lgr4 deficiency limits local myocardial inflammatory responses, inhibits leukocyte infiltration, promotes a pro-resolving macrophage phenotype, and collectively attenuates ischemic injury and facilitates cardiac repair.[52] Myeloid cell deletion of the transcription factor GATA3 also improves cardiac function in mice with cardiac injuries such as MI and cardiac pressure overload (transverse aortic constriction).[53] Finally, Vagnozzi et al[54] demonstrate that allogeneic adult stem cell transplantation activates CCR2+CX3CR1+ macrophages, alters fibroblast activity, reduces myocardial fibrosis in the infarct border zone, and improves the mechanical properties of the infarcted region.

Cardiac resident macrophages have been found to display functions distinct from monocyte-derived macrophages in inflammatory response and clearance of necrotic tissue.[38,54] However, the exact role of resident macrophages in myocardial injury and repair, and post-infarction remodeling is still unclear. Both CCR2+ and CCR2 cell populations orchestrate diverse responses following MI. CCR2+ cells facilitate monocyte recruitment into the heart following MI via CCR2-MCP1 mediated trafficking and secrete high levels of pro-inflammatory mediators, including IL-1β, TNF, and IL-6. Depletion of tissue-resident CCR2+ macrophages resulted in the improved left ventricle (LV) systolic function, smaller LV chamber dimensions, and reduced akinetic myocardium compared with controls.[43] Conversely, CCR2 macrophages appear to play an immune-modulatory, pro-regenerative role, expressing high levels of growth factors, including insulin-like growth factor 1 (IGF1) and platelet-derived growth factor C (PDGF-C). Depletion of this tissue-resident CCR2 macrophage population showed enhanced monocyte/macrophage infiltration to the heart and resulted in diminished LV systolic function, larger LV chamber dimensions, and increased akinetic myocardium.[44]

The contribution of macrophages on the survival and function of cardiac cells (cardiomyocyte, endothelial cell, fibroblast) is not fully understood due to the complexity of the in vivo inflammatory microenvironment. The crosstalk and interactions between macrophages and other cardiac cells likely play a critical role in pathological cardiac remodeling. Understanding the key cells involved and how they communicate with one another is of paramount importance for developing effective clinical treatments. Macrophages release proangiogenic and pro-reparative factors (eg, VEGF and TGF-β) and facilitate neoangiogenesis[55] and scar building.[56] Activated macrophages also secrete mir-155-enriched exosomes, which promote fibroblast inflammation, leading to an impaired cardiac repair after myocardial infarction.[57] In cultured cardiomyocytes, the pro-inflammatory macrophage-derived factors significantly downregulate cardiac troponin T and sarcoplasmic/endoplasmic reticulum calcium ATPase gene expression. In contrast, the anti-inflammatory macrophages significantly increased cardiomyocyte Ca2+ fractional release.[58] Macrophage-derived IL-1β prolongs the action potential duration, decreases potassium current, increases calcium sparks in cardiomyocytes, and promotes cardiac arrhythmia.[59] When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and may accelerate their repolarization.[37]

Numerous studies have investigated the biological and pathophysiological roles of mouse macrophages. However, our understanding of the distribution, function, and role of human cardiac macrophages remains limited. Studies have demonstrated that the concept of tissue macrophage heterogeneity is translatable to humans.[34,60] Previous studies reported that human monocytes and monocyte-derived macrophages express CCR2 as observed in murine cardiac macrophages.[61,62] In one study, Bajpai et al[34] obtained myocardial specimens from patients with ischemic heart injury that contained CCR2 embryo-derived resident macrophages, CCR2+ monocyte-derived resident macrophages, and CCR2+ monocytes. They tested LV myocardial specimens from patients with HR and found that the human heart contains distinct subsets macrophages, with CCR2+ macrophages derived from influx of blood flow and CCR2 macrophages maintained and resident in the heart. Like murine cardiac resident macrophages, which are categorized by major histocompatibility complex (MHC) expression, human cardiac macrophages can be categorized via human homolog of MHC-II human leukocyte antigen DR isotype (HLA-DR) expression. CCR2+HLA-DRhigh and CCR2HLA-DRhigh cells represent macrophages in cardiac tissue, and CCR2+HLA-DRlow cells are circulating monocytes. One distinction between murine cardiac macrophages and human cardiac macrophages is that murine CCR2 macrophages express both high and low MHC II while human CCR2 macrophages predominantly express high HLA-DR.[34] Human CCR2+ macrophages express CD14+CD16, indicating an origin from monocytes, which are predominantly CD14+CD16 and functionally equivalent to murine Ly6ChighCCR2+ monocytes.[63] Human macrophages can be distinguished from other dendritic cells by the MerTK expression.[64] Human cardiac CCR2 macrophages and CCR2+ macrophages expressed MerTK at the mRNA and protein level, while CCR2+ monocytes lacked MerTK expression. DeBerge et al[48] demonstrated that resident CCR2+ macrophages induce MerTK expression on CCR2 cardiac resident macrophages, suggesting that monitoring soluble MER serum levels can serve as an indicator of MerTK cleavage after ischemic/reperfusion injury in humans and as a prognostic marker after heart attack.

As a conclusive and prospective viewpoint, we summarized all the functions of the inflammatory cells in ischemia heart tissue during IHD, as illustrated in Figure 2. It indicates all involved inflammatory cells and their role in the pro-reparative process.

F2
Figure 2:
Illustration of functions of inflammatory cells in ischemic heart disease. Following acute myocardial infarction, endothelial cells within the heart are activated. Mast cells, which are located in perivascular areas, are also activated. Endothelial cells and mast cells produce various cytokines, which trigger the postinfarction inflammatory response. Circulating neutrophils and monocytes are recruited to the ischemic zone, in which monocytes are differentiated to macrophages. Neutrophils, monocytes, and macrophages induce the pro-inflammatory response and cardiac remodeling by releasing cytokines (such as IL-1β, IL-6, TNF, CXCL2, CXCL5, CCL2, CCL7). Cardiac resident macrophages (including CCR2-Ly6ClowMHCIIlow and CCR2-Ly6ClowMHCIIhigh subgroups), on the other hand, induce the anti-inflammatory response and cardiac repair by releasing IGF1, PDGF-C, and MerTK. CCL: CC-chemokine ligand; CCR: C-C chemokine receptor; CXCL: Chemokine C-X-C motif ligand; IGF1: Insulin-like growth factor 1; IL: Interleukin; MerTK: Myeloid-epithelial reproductive tyrosine kinase; PDGF-C: Platelet-derived growth factor C; TNF: Tumor necrosis factor.

Perspective

The heart harbors a heterogeneous group of macrophages that can participate in both pro-inflammatory and pro-reparative processes. The distinction between tissue-residing cardiac macrophages and circulating monocyte-derived macrophages has become a fertile area for study in recent years.[22] CCR2+ resident macrophages play roles in neutrophils recruitment and pro-inflammation and are associated with adverse heart remodeling and impaired LV systolic function. In contrast, CCR2 resident macrophages participate in the cardiac wound phagocytotic debridement and pro-reparative processes and are associated with improved heart outcomes. These findings highlight that macrophages, whether circulating or permanently residing, originate from diverse lineages, and as a result, have different functions.

Together, these study findings suggest that interventions that target CCR2+ macrophages with subsequent improvement of CCR2 resident macrophage function may represent a novel therapeutic approach to suppressing inflammation and decreasing adverse LV remodeling in post-MI patients, thus improving their long-term heart function. Future studies are needed to determine the beneficial and adverse physiologic and pathophysiologic effects of resident macrophages in human cardiac tissue and their potential clinical use in controlling infarct size and reversing adverse cardiac remodeling to improve mortality in post-MI patients.

Funding

None.

Conflicts of Interest

None.

Editor note: Xinliang Ma is an associate editor of Cardiology Discovery. Yajing Wang is a member of the editorial board of Cardiology Discovery. The article was subject to the journal's standard procedures, with peer review handled independently of these editors and their research groups.

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Keywords:

Acute myocardial infarction; Heart failure; Immunoregulation therapy; Inflammation; Macrophages

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