Comprehensive macro and micro views on immune cells in ischemic heart disease

FIGURE 1. Immune cells in the cardiovascular system. After AMI, monocytes are recruited to cardiac tissue and differentiate into M1 and M2 macrophages. M1 macrophages induce vascular inflammation by releasing DAMPs, and M2 macrophages promote damaged tissue repair by producing VEGF, among others. Pro‐inflammatory cytokines induce neutrophil infiltration, and neutrophils mediate the release of ROS through neutrophil NETosis and secrete inflammatory cytokines that exacerbate and sustain the inflammatory response. Infiltrating CD4+ cells include helper T cells (Th1 and Th1 cells reduce the fibrotic response, while Th2 and Th17 cells promote fibrosis. Th17 cells also promote inflammation and extracellular matrix remodelling, while Treg cells attenuate the inflammatory response). Mast cells promote fibrosis, and angiogenesis and promote fibroblast proliferation and collagen synthesis via TNF‐α. NK cells reduce cardiac eosinophil infiltration and prevent the maturation and transport of inflammatory cells. DCs induce myocardial hypertrophy and improve ventricular remodelling by mediating the increase in Treg activity. The secretion of cytokines such as IL‐10 by NKT cells plays a role in…

FIGURE 2. Monocyte differentiation after AMI. During IHD, bone marrow‐derived monocytes are recruited to the damaged myocardial tissue and subsequently differentiate to form M1 macrophages and M2 macrophages stimulated by GM‐CSF and M‐CSF. M1 macrophages possess markers such as TLR‐2, TLR‐4, CD80, and CD86 and produce pro‐inflammatory cytokines including IL‐1β, TNF‐α, and CCL5, which induce M2 macrophages to express markers such as CD163, CD206, and FIZZ1, and produce anti‐inflammatory cytokines including IL‐10, TNF‐β, and VEGF, which induce tissue repair.

FIGURE 3. Macrophage‐mediated‐remodelling of two opposing ventricles after infarction. After AMI caused by multiple factors, myocardial cells die in large numbers and inflammatory cells infiltrate into the damaged tissue to mediate the repair response after injury. Monocytes recruited from the bone marrow differentiate in the damaged tissue to form macrophages, which subsequently differentiate into pro‐inflammatory M1 macrophages and anti‐inflammatory M2 macrophages. In the post‐infarction repair phase, if M1 macrophages persist, they lead to long‐term maintenance of the inflammatory response, which in turn leads to adverse ventricular remodelling and eventually heart failure; if M1 macrophages are able to dissipate, M2 macrophages play a key role in the repair phase, producing anti‐inflammatory and repair mediators that induce benign ventricular remodelling.

FIGURE 4. TGF‐β signalling cascade response mediates fibroblast activation after AMI to induce fibrosis. TGF‐β is a major cytokine regulating fibrosis, and its release is regulated by both M1/M2 macrophages. TGF‐β has regulatory effects on endothelial cells, cardiomyocytes, Tregs, regulatory macrophages, and fibroblasts. TGF‐β binds to its type I and type II receptors through integrin‐mediated contractile release, activating the typical Smad3/4 pathway and the atypical TGF‐β‐activated kinase‐1 (TAK‐1)‐p38/c‐Jun N‐terminal kinase (JNK) and NADPH oxidase 4 (NOX4)/ROS pathways, which induce fibrotic genes such as α smooth muscle actin (α‐SMA), collagen and CCN2, to promote extracellular matrix synthesis.

FIGURE 5. Neutrophil activation and recruitment. During IHD, neutrophils accumulate at the injury site and induce an acute inflammatory response. These neutrophils, through NETosis, release S100A8/A9 into the infarct area, which acts on TLR4 on the cell membrane and causes the release of IL‐1β from the NLRP3 inflammasome on nascent neutrophils, which binds to IL‐1R on HSPCs in the bone marrow, thereby promoting neutrophil recruitment and activation.

FIGURE 6. Activation of inflammatory vesicles by neutrophils after AMI induces cell necrosis and apoptosis. After AMI, inflammatory tissue‐recruited macrophages release DAMPs (ATP, mtRNA, RNA and HMBGB1) to exacerbate the inflammatory response, and these inflammatory signalling factors mediate cardiomyocyte death by acting on TLRs, causing intracellular calcium overload and ROS production, promoting RLRP3 inflammatory vesicle formation, or bind to neutrophil surface receptors, causing neutrophil activation, inducing a sustained inflammatory response, which in turn leads to apoptotic cellular tissue necrosis.