Neutrophil death pathways in myocardial infarction: the balance between injury and repair

Figures

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  Figure 1. Temporal dynamics of neutrophil death pathways after myocardial infarction. The schematic summarizes stage-specific shifts in neutrophil recruitment, NETosis/protease release, apoptosis/efferocytosis, and late remodeling after MI. MI, myocardial infarction; NETosis, neutrophil extracellular trap formation; DAMPs, damage-associated molecular patterns; ROS, reactive oxygen species; MPO, myeloperoxidase.

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  Figure 2. Context-dependent roles of MMP-9 and MMP-12 in post-MI neutrophil apoptosis and repair. MMP-9 promotes CD36 degradation, reduces macrophage phagocytosis/efferocytosis, directly suppresses neutrophil apoptosis in vitro, and may prolong inflammation, whereas MMP-12 is linked to CD44-hyaluronan signaling, neutrophil apoptosis, and inflammation resolution. MI, myocardial infarction; MMP, matrix metalloproteinase; CD36, cluster of differentiation 36; HA, hyaluronan; CD44, cluster of differentiation 44; ECM, extracellular matrix.

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  Figure 3. Neutrophil-macrophage crosstalk in post-MI cardiac repair. Following acute MI, neutrophils infiltrate the infarcted myocardium and release neutrophil-derived mediators such as Annexin A1 and cytokines, which modulate macrophage polarization into either pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. M1 macrophages secrete mediators like IL-1β and TNF-α, whereas M2 macrophages produce tissue-repair factors such as IL-10 and TGF-β. These macrophage-derived signals reciprocally regulate neutrophil apoptosis: timely apoptosis enables efficient efferocytosis by macrophages, triggering the release of anti-inflammatory and reparative mediators (e.g., IL-10, TGF-β) that resolve inflammation and promote tissue repair. Conversely, delayed neutrophil apoptosis synergizes with M1 macrophages to amplify inflammation, perpetuating neutrophil recruitment and macrophage activation. Furthermore, neutrophil-derived mediators shape macrophage phagocytic capacity through phenotypic reprogramming. Dysregulation of this axis—whether due to impaired apoptosis or defective efferocytosis—fuels persistent inflammation, exacerbates cardiac injury, and impedes repair, underscoring the pivotal…

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  Figure 4. Mechanisms of thromboinflammation: platelet-neutrophil crosstalk and NETosis in coronary thrombus formation. Endothelial injury and reduced blood velocity at sites of coronary artery stenosis promotes neutrophil recruitment and platelet activation. Activated platelets release mediators such as HMGB1, polyP, and CXCL4, which induce neutrophil extracellular trap (NET) formation—a process termed NETosis. NETosis is a distinct form of programmed neutrophil death characterized by chromatin extrusion and release of cytotoxic granular proteins, forming web-like structures termed NETs. These NETs act as scaffolds that bind platelets, fibrin, and coagulation factors, amplifying thromboinflammation. At atherosclerotic plaques, activated platelets, fibrin, red blood cells and NETotic neutrophils accumulate synergistically, driving occlusive thrombus formation. NET-driven thromboinflammation perpetuates a vicious cycle: platelet activation enhances NETosis, while NETs further recruit and activate platelets and neutrophils, exacerbating vascular injury. This interplay underscores the critical role of platelet-neutrophil crosstalk and dysregulated NETosis in coronary thromboinflammatory…