Platelet-macrophage crosstalk in cardiac inflammation and remodeling

Cardiac injury and chronic heart disease are increasingly recognized as multicellular processes driven by dynamic interactions between immune and thrombotic signaling networks. Although platelets and macrophages have been extensively studied individually, the molecular mechanisms through which their reciprocal interactions regulate cardiac inflammation and remodeling remain incompletely defined. A comprehensive understanding of this cellular crosstalk is needed to define the signaling pathways that couple acute injury responses to chronic maladaptive remodeling. Among these interactions, platelet-macrophage crosstalk has emerged as an important regulator of inflammatory responses and tissue remodeling within the injured myocardium. Beyond their traditional roles in hemostasis and innate immunity, platelets communicate with macrophages through adhesion molecules, soluble mediators, and extracellular vesicles, thereby modulating macrophage activation and functional reprogramming. Platelet-derived mediators, including P-selectin, CD40L, PF4 (CXCL4), CCL5, and platelet-derived extracellular vesicles, modulate macrophage inflammatory signaling, cytokine production, redox balance, metabolic reprogramming, and pro-fibrotic responses relevant to cardiac remodeling. During acute myocardial injury, these interactions facilitate immune-cell recruitment, efferocytosis, and tissue repair, whereas persistent platelet-macrophage communication promotes chronic inflammation, extracellular matrix remodeling, and progression to heart failure. This review summarizes current molecular insights into platelet-macrophage interactions, focusing on receptor-mediated signaling, extracellular vesicle cargo transfer, immunometabolic regulation, and redox-dependent pathways. We also discuss emerging evidence linking this axis to trained immunity and inflammatory memory and highlight potential molecular targets for modulating maladaptive immune remodeling in cardiovascular disease.