Neutrophil extracellular traps promote scar formation in post-epidural fibrosis

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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.

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Most cited references 47

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Macrophages in Tissue Repair, Regeneration, and Fibrosis.

Thomas Wynn, Kevin Vannella (2016)

Inflammatory monocytes and tissue-resident macrophages are key regulators of tissue repair, regeneration, and fibrosis. After tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, such that uncontrolled production of inflammatory mediators and growth factors, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contribute to a state of persistent injury, and this could lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound-healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue-regenerating phenotypes after injury, and we highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically.

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Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice

Jean Albrengues, Mario A. Shields, David Ng … (2018)

Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to awaken, resume proliferating, and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin α3β1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.

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Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.

Siu Wong, Mélanie Demers, Kimberly Martinod … (2015)

Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.

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Author and article information

Contributors

Jun Liu:

ORCID: http://orcid.org/0000-0003-3756-3627

13776698080@139.com

Mingshun Zhang:

ORCID: http://orcid.org/0000-0001-5925-0168

mingshunzhang@njmu.edu.cn

Journal

Journal ID (nlm-ta): NPJ Regen Med

Journal ID (iso-abbrev): NPJ Regen Med

Title: NPJ Regenerative Medicine

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2057-3995

Publication date (Electronic): 30 October 2020

Publication date PMC-release: 30 October 2020

Publication date Collection: 2020

Volume: 5

Electronic Location Identifier: 19

Affiliations

[1 ]GRID grid.452511.6, Department of Orthopaedics, , The Second Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu 210011 China

[2 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Respiratory and Critical Care Medicine, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, 210029 China

[3 ]GRID grid.89957.3a, ISNI 0000 0000 9255 8984, NHC Key Laboratory of Antibody Technique, Department of Immunology, Nanjing Medical University, ; Nanjing, 211166 China

Author information

Zhen Jin http://orcid.org/0000-0003-3647-9845

Yap San Min Nicolas http://orcid.org/0000-0001-7126-9793

Jun Liu http://orcid.org/0000-0003-3756-3627

Mingshun Zhang http://orcid.org/0000-0001-5925-0168

Article

Publisher ID: 103

DOI: 10.1038/s41536-020-00103-1

PMC ID: 7599244

PubMed ID: 33298919

SO-VID: 86f83817-08a4-4f87-b41e-8921d4806af6

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 12 October 2019

Date accepted : 25 September 2020

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81671563

Award Recipient : Mingshun Zhang

Funded by: Jiangsu Provincial Commission of Health and Family Planning (Jun Liu), "Six One" Project of Jiangsu province LGY2016018 (Jun Liu) and Jiangsu Provincial Personnel Department "the Great of Six Talented Man Peak" Project WSW-040 (Jun Liu)