Neutrophil extracellular traps, pain amplification, and brain–heart interactions: A narrative review with a neuro-immune perspective

Neutrophil extracellular traps (NETs) are increasingly recognized as key effectors of innate immune activation and drivers of inflammatory tissue injury. Beyond their established role in host defense, experimental and translational studies suggest that NETs may contribute to pain amplification through mechanisms that affect the peripheral, central, and cardiovascular systems. This review synthesizes current research on the role of NETs as pain amplifiers, with a special focus on their involvement in microvascular dysfunction, immune-mediated ischemia, neuro-immune crosstalk, and autonomic dysregulation. By influencing endothelial integrity and microcirculatory function, NET-driven processes serve as common pathophysiological factors connecting cardiovascular vulnerability and neural tissue stress. Persistent NET-associated inflammatory signaling may also contribute to central sensitization and maladaptive brain–heart interactions. Within this integrated framework, pain is understood not only as a localized symptom but also as a potential clinical indicator of systemic neuro-immune and neurovascular stress along the brain-heart axis. Framing NETs as upstream modifiers of neuro-immune and neurovascular disease offers a unifying perspective on pain, cardiovascular issues, and central nervous system vulnerability. This mechanism-based view may enhance risk assessment and highlight NET-related pathways as potential targets for personalized treatment in patients with complex brain–heart disease interactions.