Neutrophil extracellular traps in diabetic wound healing: mechanisms, pathological roles, and therapeutic implications

Abstract

Diabetic wound healing is a common yet challenging problem in clinical practice that involves complex pathophysiological processes and frequently progresses to chronic nonhealing wounds, imposing substantial burdens on both healthcare systems and patients while markedly decreasing quality of life. Persistent inflammatory responses represent a fundamental pathological feature of this condition. Accumulating evidence highlights the key role of neutrophil extracellular traps (NETs) in the chronic inflammatory response characteristic of diabetic wounds. As components of the innate immune system, NETs play pivotal roles in both host defence and tissue repair. Neutrophil extracellular trap formation (NETosis) is currently classified as vital NETosis or lytic NETosis. In this review, we synthesize existing evidence on the mechanistic heterogeneity of NETosis and further refine lytic NETosis subtypes on the basis of distinct molecular mechanisms and temporal dynamics-namely, NADPH oxidase 2 (NOX2)-dependent classical lytic NETosis and mitochondrial reactive oxygen species–driven rapid lytic NETosis. We also highlight the functional outcomes of NETs in response to specific stimuli within the diabetic wound milieu. Therapeutic strategies targeting NET formation, degradation, or neutralization have shown considerable promise in preclinical studies; however, their clinical translation will require standardized biomarkers for NET quantification, localized delivery approaches to minimize systemic immunosuppression, and biomarker-guided frameworks to balance the risk of infection against healing benefits.

Keywords

Neutrophil extracellular traps / Neutrophil extracellular trap formation / Diabetic wounds / Chronic inflammation / Wound healing

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