Tissue-Resident Macrophages in Cardiovascular Diseases: Heterogeneity and Therapeutic Potential

Figures

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  Figure 1. Phenotyping and Functions of Resident Macrophages. (A) Resident macrophages are divided into M1 and M2 subtypes. M1 macrophages secrete pro-inflammatory cytokines like TNF-α and IL-1β, promoting inflammation, while M2 macrophages secrete IL-10 and TGF-β, suppressing inflammation and moderately regulating fibrosis. Metabolic reprogramming plays a key role in the differentiation of M1 and M2. (B) Cardiac resident macrophages (CRMs) can be classified into CCR2+ and CCR2− subtypes. CCR2+ macrophages, derived mainly from bone marrow monocytes, promote fibrosis and inflammation. CCR2− macrophages, originating from the yolk sac and fetal liver, have anti-fibrotic and anti-inflammatory functions. (C) CRMs are further subdivided into LYVE1^hi MHC-II^lo and LYVE1^lo MHC-II^hi subsets. LYVE1^hi MHC-II^lo macrophages are located around blood vessels and may maintain vascular stability, while LYVE1^lo MHC-II^hi macrophages are found near nerve fibers and may be involved in neural regulation, antigen presentation, and heart rhythm control.

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  Figure 2. Dynamic Changes in Cardiac Resident Macrophages During Myocardial Infarction. The pathological progression of myocardial infarction (MI) can be divided into three phases: the inflammatory phase (0–2 days), the proliferative repair phase (3–7 days), and the maturation phase (7–14 days). Both CCR2+ and CCR2− CRMs undergo a process of initial decline, followed by an increase, and then a subsequent decline. These CCR2− macrophages play a protective role by reducing inflammation, preventing fibrosis, and promoting tissue repair through the secretion of TGF-β, IGF-1, and Platelet Derived Growth Factor C (PDGF-C). Conversely, CCR2+ macrophages contribute to chronic inflammation, fibrosis, and adverse cardiac remodeling by secreting TNF-α and IL-1β.

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  Figure 3. Dynamic Changes in Cardiac Resident Macrophages During Heart Failure. In the early stages of heart failure, CCR2+ macrophages quickly migrate to injury sites, releasing pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6, which worsen inflammation, fibrosis, and cardiac remodeling. As the disease progresses, their numbers decrease. In contrast, CCR2− macrophages provide protection early on but decline due to depletion, and they recover through proliferation in later stages. They contribute to anti-inflammatory and anti-fibrotic effects by secreting IGF-1 and TGF-β.

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  Figure 4. Origins and Role of Arterial-resident Macrophages in Atherosclerotic Plaque Formation and Progression. Macrophages originate from three sources: the primitive yolk sac, fetal liver monocytes, and bone marrow monocytes. Among them, macrophages derived from the first two sources are known as arterial-resident macrophages, which represent the predominant type of macrophage in the arterial intima under homeostatic conditions. Arterial-resident macrophages have the ability to engulf lipids and form the first foam cells within plaques, establishing the core of early plaque lesions. Additionally, they facilitate the chemotaxis of bone marrow monocytes to the subintimal space, thereby contributing to the initiation and growth of plaques. In the figure, dashed arrows indicate the movement trajectories of molecules or cells, while solid arrows represent transitions between distinct cell types.

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  Figure 5. The Role of Different Subtypes of Arterial-resident Macrophages in Atherosclerotic Plaques and Cardiovascular Diseases. Arterial-resident macrophages exhibit heterogeneity and can be classified into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. In AS plaques, M1 macrophages are primarily located in unstable regions of the plaque, such as the shoulder and lipid core, areas prone to rupture, thereby accelerating the progression of AS and potentially leading to acute cardiovascular events, such as myocardial infarction. In contrast, M2 macrophages are mainly found in more stable regions, such as the fibrous cap of the plaque, where they help slow the progression of AS and reduce the incidence of acute cardiovascular diseases.

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  Figure 6. The Role of Glucose Metabolic Reprogramming in Regulating Arterial-resident Macrophage Differentiation into M1 and M2 Subtypes. In unstable regions of atherosclerotic plaques, like the plaque shoulder and necrotic core, factors such as hypoxia, hyperglycemia, and inflammatory signals increase glycolysis in arterial-resident macrophages while reducing mitochondrial oxidative phosphorylation (OXPHOS). This metabolic reprogramming drives more differentiation into pro-inflammatory M1 macrophages and less into anti-inflammatory M2 macrophages. Glycolysis also promotes the release of pro-inflammatory factors like IL-1β and ROS, worsening M1-induced tissue damage. In contrast, in more stable plaque areas, where oxygen supply is sufficient, glycolysis decreases, while OXPHOS and the TCA cycle are enhanced. This shift favors M2 differentiation, reducing M1 macrophages. M2 macrophages secrete anti-inflammatory mediators such as IL-10 and TGF-β, which help stabilize the plaque. In the figure, solid arrows depict activating or inhibitory effects of various factors within the plaque microenvironment on metabolic reprogramming pathways, while dashed arrows indicate pro-inflammatory or…

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  Figure 7. The Role of Fatty Acid Metabolic Reprogramming in Regulating Arterial-resident Macrophage Differentiation into M1 and M2 Subtypes. In unstable areas of the plaque, such as the shoulder and lipid core, hypoxia triggers the activation of HIF-1α. Additionally, metabolites like citrate within the plaque enhance FAS, which in turn promotes the differentiation of arterial-resident macrophages into the pro-inflammatory M1 subtype. The fatty acids produced through this process also encourage foam cell formation, further accelerating the progression of atherosclerosis. By contrast, in more stable regions of the plaque, such as the fibrous cap, where oxygen is sufficiently available, HIF-1α is suppressed. The relative energy scarcity in these regions activates AMPK, stimulating FAO. This process provides a crucial energy source for macrophages and supports their differentiation into the anti-inflammatory M2 subtype. In the figure, solid arrows depict activating or inhibitory effects on fatty acid metabolic pathways or key molecules involved, while dashed arrows indicate resultant metabolites.