At the heart of inflammation: Unravelling cardiac resident macrophage biology

Figures

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  FIGURE 1. Categorization and origins of CRMs. The categorization and origins of CRMs are delineated based on their expression of C‐C chemokine receptor 2 (CCR2). Under physiological conditions within the heart, two primary macrophage subtypes emerge: Those derived from embryonic origins and those originating from the bone marrow. Embryonic‐derived macrophages: These macrophages originate from the yolk sac and fetal liver during embryonic development. They express CCR2‐ and possess the capacity for self‐renewal, thus designated as CRMs. Research indicates that these macrophages predominantly manifest MHCIIlo and CCR2− expression and exhibit characteristic marker gene profiles, including TimD4+, Lyve1+ and FolR2+, hence denoted as TLF+ macrophages (A). Bone marrow‐derived macrophages: These macrophages stem from mature monocytes and express CCR2+. In the early stages of development, CCR2+ macrophages migrate into the heart and sustain their population through continual recruitment and proliferation of monocytes. In contrast to embryonic‐derived macrophages, these CCR2+ macrophages demonstrate a propensity toward pro‐inflammatory functions (B).

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  FIGURE 2. Role of cardiac macrophages in cardiac development, homeostasis and response to injury. Under stable conditions, these macrophages help maintain the heart's internal environment. CCR2− macrophages promote vascular maturation in coronary arteriogenesis through vasodilation, potentially mediated by IGF1 and IGF2. They also support lymphatic capillary development in the heart and prevent cardiac conduction issues. Resident macrophages play a key role in maintaining mitochondrial homeostasis, clearing dysfunctional mitochondria to enhance cardiac function (A). They also contribute to vascular oxidative stress and may vary in their impact on myocarditis. Macrophages participate in cardiac regeneration processes through vegfaa expression. Neonatal macrophages facilitate myocardial regeneration through myocardial cell proliferation and angiogenesis (B).

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  FIGURE 3. Macrophages dynamics in myocardial infarction. The mouse MI model progresses through three stages within a few short days: Inflammation, anti‐inflammatory and repair. Acute MI triggers significant inflammation, leading to extensive necrosis of cardiomyocytes in the infarct area. F4/80lowLy6Chigh monocytes predominantly infiltrate, while CRMs and fibroblasts proliferate, releasing cytokines like IL‐6, IL‐1β and TNFα. By day 3, inflammation‐related gene expressions decrease, macrophages enhance phagocytosis and proliferation and pro‐inflammatory macrophages undergo apoptosis. MHC‐IIlowCCR2− macrophages express legumain (Lgmn) during this stage. By day 7, macrophages secrete extracellular matrix proteins and cytokines like IL‐10, TGFβ and VEGFα, indicative of repair.