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REVIEW ARTICLE

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

Chiara Angeletti1* ,  Ernesto Aitella2 ,  Valentina Arcangeli1 ,  Sofia Ranieri Chiatamone3 ,  Giustino Varrassi4
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1 Department of Anesthesiology, Intensive Care and Pain Medicine, Civil Hospital G. Mazzini of Teramo, Teramo, Italy
2 Department of Life, Health and Environmental Sciences, University of L’Aquila, Allergy and Clinical Immunology Unit, Center for the Diagnosis and Treatment of Osteoporosis, Teramo, Italy
3 Pathology Unit, Department of Services, Civil Hospital G. Mazzini of Teramo, Teramo, Italy
4 Department of Research, Fondazione Paolo Procacci, Rome, Italy
Brain & Heart, 026060007 https://doi.org/10.36922/BH026060007
Received: 6 February 2025 | Revised: 10 March 2026 | Accepted: 17 March 2026 | Published online: 17 April 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

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.

Keywords
Neutrophil extracellular traps
Pain amplification
Neuro-immune mechanisms
Microvascular dysfunction
Brain–heart axis
Autonomic dysregulation
Cardiovascular disease
Central sensitization
Funding
None.
Conflict of interest
Giustino Varrassi is an Editorial Board Member of this journal and Guest Editor of this Special Issue, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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