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Neutrophil extracellular traps promote scar formation in post-epidural fibrosis.

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-?B 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.

SUBMITTER: Jin Z

PROVIDER: S-EPMC7599244 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Neutrophil extracellular traps promote scar formation in post-epidural fibrosis.

Jin Zhen Z Sun Jinpeng J Song Zeyuan Z Chen Kun K Nicolas Yap San Min YSM Kc Rupesh R Ma Qiyun Q Liu Jun J Zhang Mingshun M

NPJ Regenerative medicine 20201030 1

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 ...[more]

PMID: 33298919

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Project description:The inflammatory microenvironment is commonly characterized by extracellular acidosis (pH < 7.35). Sensitivity to pH, CO2 or bicarbonate concentrations allows neutrophils to react to changes in their environment and to detect inflamed areas in the tissue. One important antimicrobial effector mechanism is the production of neutrophil extracellular traps (NETs), which are released during a programmed reactive oxygen species (ROS)-dependent cell death, the so-called NETosis. Although several functions of neutrophils have been analyzed under acidic conditions, the effect of extracellular acidosis on NETosis remains mainly unexplored and the available experimental results are contradictory. We performed a comprehensive study with the aim to elucidate the effect of extracellular acidosis on ROS-dependent NETosis of primary human neutrophils and to identify the underlying mechanisms. The study was performed in parallel in a CO2-bicabonate-buffered culture medium, which mimics in vivo conditions, and under HEPES-buffered conditions to verify the effect of pH independent of CO2 or bicarbonate. We could clearly show that extracellular acidosis (pH 6.5, 6.0, and 5.5) and intracellular acidification inhibit the release of ROS-dependent NETs upon stimulation of neutrophils with phorbol myristate acetate and immobilized immune complexes. Moreover, our findings suggest that the diminished NET release is a consequence of reduced ROS production and diminished glycolysis of neutrophils under acidic conditions. It was suggested previously that neutrophils can sense the border of inflamed tissue by the pH gradient and that a drop in pH serves as an indicator for the progress of inflammation. Following this hypothesis, our data indicate that an acidic inflammatory environment results in inhibition of extracellular operating effector mechanisms of neutrophils such as release of ROS and NETs. This way the release of toxic components and tissue damage can be avoided. However, we observed that major antimicrobial effector mechanisms such as phagocytosis and the killing of pathogens by neutrophils remain functional under acidic conditions.

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Neutrophil extracellular traps promote scar formation in post-epidural fibrosis.

Publications

Neutrophil extracellular traps promote scar formation in post-epidural fibrosis.

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