Neutrophil extracellular traps promote scar formation in post-epidural fibrosis

Zhen Jin,Qiyun Ma,Jun Liu,Yap San Min Nicolas,Jinpeng Sun,Kun Chen,Mingshun Zhang,Rupesh Kc,Zeyuan Song

doi:10.1038/s41536-020-00103-1

Abstract

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.

Highlights

Excessive scar formation is one of the main concerns in spine surgery
To explore whether Neutrophil extracellular traps (NETs) were involved with post-epidural fibrosis, we sampled peripheral blood and wound drainage from patients receiving spine surgery
In the follow-up study, we noticed a patient with high NETs developed excessive epidural fibrosis (Fig. 1d), suggesting that NETs, may influence the process of scar formation in the patients receiving spine operation

Summary

Introduction

Excessive scar formation is one of the main concerns in spine surgery. Numerous biological methods to reduce scar formation after spine surgery have been postulated by our team[2,3,4] and other labs[5,6,7]. As the most abundant leukocytes in the blood, neutrophils migrate into injured tissues and contribute to wound healing[8]. NETs have been linked to cystic fibrosis[15], but may impair wound healing in diabetes[16]. NETs and associated enzymes promote the differentiation of fibroblasts into myofibroblasts accompanied with increased α smooth muscle actin (α-SMA) and collagen I NETs and associated enzymes promote the differentiation of fibroblasts into myofibroblasts accompanied with increased α smooth muscle actin (α-SMA) and collagen I (ref. 17)

Methods

Results

Conclusion