Neutrophil extracellular traps promote scar formation in post-epidural fibrosis

Low back pain following spine surgery is a major complication due to excessive epidural fibrosis, which compresses the lumbar nerve. The mechanisms of epidural fibrosis remain largely elusive. In the drainage samples from patients after spine operation, neutrophil extracellular traps (NETs) and NETs inducer high-mobility group box 1 were significantly increased. In a mouse model of laminectomy, NETs developed in the wound area post epidural operation, accompanied with macrophage infiltration. In vitro, macrophages ingested NETs and thereby increased the elastase from NETs via the receptor for advanced glycation end product. Moreover, NETs boosted the expression of fibronectin in macrophages, which was dependent on elastase and could be partially blocked by DNase. NF-κB p65 and Smad pathways contributed to the increased expression fibronectin in NETs-treated macrophages. In the mouse spine operation model, post-epidural fibrosis was significantly mitigated with the administration of DNase I, which degraded DNA and cleaved NETs. Our study shed light on the roles and mechanisms of NETs in the scar formation post spine operation.