The emerging roles of neutrophil extracellular traps in wound healing

Abstract

Delayed wound healing causes problems for many patients both physically and psychologically, contributing to pain, economic burden, loss of function, and even amputation. Although many factors affect the wound healing process, abnormally prolonged or augmented inflammation in the wound site is a common cause of poor wound healing. Excessive neutrophil extracellular trap (NET) formation during this phase may amplify inflammation and hinder wound healing. However, the roles of NETs in wound healing are still unclear. Herein, we briefly introduce NET formation and discuss the possible NET-related mechanisms in wound healing. We conclude with a discussion of current studies, focusing on the roles of NETs in diabetic and normoglycemic wounds and the effectiveness of NET-targeting treatments in wound healing.

Fig. 1. Three types of NET formation.

a The first type is classic suicidal NET formation, which is characterized by nuclear chromatin decondensation, NET release, membrane rupture, and cell death. b The second type is vital NET formation; after releasing NETs, neutrophils are intact and remain phagocytic. c The third type is mitochondrial DNA NET formation, which triggers NET formation from mitochondrial DNA but not nuclear DNA.

Fig. 2. Mechanisms of NET effects on wound healing.

Excessive amounts of NET components such as neutrophil elastase, MPO, and MMPs can destroy wound structures, including collagen, fibronectin, and cellular matrix. In addition, NETs impair angiogenesis in the wound area. NETs also affect the number or functions of wound-repairing cells, eventually leading to delayed wound healing.

Fig. 3. Roles of NETs in diabetic and normoglycemic mouse wounds.

A In diabetic mouse wounds, NET formation is increased, and inflammation is sustained by the NLRP3 inflammasome-NET loop due to macrophage activation and MFG-E8 deficiency. Increased LRG1 in hyperglycemic mouse blood has been shown to upregulate NET formation via the Akt pathway. PKC βII exhibits hyperactivity in diabetes and contributes to excess NET formation. In addition, GnRH expressed on neutrophils enhances NET formation in the wound area. B In normoglycemic wounds, dectin-2 increases the neutrophil inflammatory response and NET formation. Neutrophil-derived FXII modulates neutrophil NET formation by upregulating αMβ2 integrin and increasing intracellular calcium.