Neutrophil extracellular traps promote scar formation in post-epidural fibrosis

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

doi:10.1038/s41536-020-00103-1

Cited by 24 publications

(18 citation statements)

References 45 publications

(51 reference statements)

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“…We also observed that living microglia and neutrophils increase their ET formation following durotomy. This result correlates with other studies demonstrating the formation of NETs by infiltrating neutrophils in mouse models of durotomy (Jin et al, 2020). However, this is the first report of MiET formation in the spinal cord following durotomy.…”

Section: Discussionsupporting

confidence: 92%

Extracellular traps formation following cervical spinal cord injury

Michel‐Flutot

Bourcier

Gasser

et al. 2022

Eur J of Neuroscience

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Spinal cord injuries involve a primary injury that can lead to permanent loss of function and a secondary injury associated with pathologic and inflammatory processes. Extracellular traps are extracellular structures expressed by immune cells that are primarily composed of chromatin, granular enzymes and histones. Extracellular traps are known to induce tissue damage when overexpressed and could be associated in the occurrence of secondary damage.In the present study, we used flow cytometry to demonstrate that at 1 day following a C2 spinal cord lateral hemisection in male Swiss mice, resident microglia form vital microglia extracellular traps, and infiltrating neutrophils form vital neutrophil extracellular traps. We also used immunolabelling to show that microglia near the lesion area are most likely to form these microglia extracellular traps. As expected, infiltrating neutrophils are located at the site of injury, though only some of them engage in post-injury extracellular trap formation. We also observed the formation of microglia and neutrophil extracellular traps in our sham animal models of durotomy, but formation was less frequent than following the C2 hemisection. Our results demonstrate for the first time that microglia form extracellular traps in the spinal cord following injury and durotomy. It remains however to determine the exact mechanisms and kinetics of neutrophil and microglia extracellular traps formation following spinal cord injury. This information would allow to better mitigate this inflammatory process that may contribute to secondary injury and to effectively target extracellular traps to improve functional outcomes following spinal cord injury.

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Section: Discussionsupporting

confidence: 92%

Extracellular traps formation following cervical spinal cord injury

Michel‐Flutot

Bourcier

Gasser

et al. 2022

Eur J of Neuroscience

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“…Several studies have demonstrated that NETs are implicated in atherosclerosis, fibrosis and thrombotic CVD (18)(19)(20). Thus, we first used ELISA to measure the levels of MPO/DNA complexes and citrullinated histone H3 (CitH3), well-defined circulating markers of NET release (14), in the plasma of EH treatment-naïve (untreated) patients.…”

Section: Increased Levels Of Circulating Nets In Untreated Newly-diagnosed Eh Patientsmentioning

confidence: 99%

Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension

Chrysanthopoulou¹,

Gkaliagkousi²,

Lazaridis³

et al. 2021

JCI Insight

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Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.

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“…NETs stimulated by free fatty acids may influence monocyte-derived macrophage infiltration and inflammation in the liver [ 39 ]. In the animal model of post-epidural fibrosis, NETs were found to increase the production of extracellular matrix components in macrophages [ 40 ]. In a systemic vasculitis known as deficiency of ADA2, NETs induced production of inflammatory cytokines from macrophages through NF-κB nuclear translocation in macrophages [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

GSDMD-dependent neutrophil extracellular traps promote macrophage-to-myofibroblast transition and renal fibrosis in obstructive nephropathy

Wang

Chen

et al. 2022

Cell Death Dis

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Renal fibrosis is a common consequence of various progressive nephropathies, including obstructive nephropathy, and ultimately leads to kidney failure. Infiltration of inflammatory cells is a prominent feature of renal injury after draining blockages from the kidney, and correlates closely with the development of renal fibrosis. However, the underlying molecular mechanism behind the promotion of renal fibrosis by inflammatory cells remains unclear. Herein, we showed that unilateral ureteral obstruction (UUO) induced Gasdermin D (GSDMD) activation in neutrophils, abundant neutrophil extracellular traps (NETs) formation and macrophage-to-myofibroblast transition (MMT) characterized by α-smooth muscle actin (α-SMA) expression in macrophages. Gsdmd deletion significantly reduced infiltration of inflammatory cells in the kidneys and inhibited NETs formation, MMT and thereby renal fibrosis. Chimera studies confirmed that Gsdmd deletion in bone marrow-derived cells, instead of renal parenchymal cells, provided protection against renal fibrosis. Further, specific deletion of Gsdmd in neutrophils instead of macrophages protected the kidney from undergoing fibrosis after UUO. Single-cell RNA sequencing identified robust crosstalk between neutrophils and macrophages. In vitro, GSDMD-dependent NETs triggered p65 translocation to the nucleus, which boosted the production of inflammatory cytokines and α-SMA expression in macrophages by activating TGF-β1/Smad pathway. In addition, we demonstrated that caspase-11, that could cleave GSDMD, was required for NETs formation and renal fibrosis after UUO. Collectively, our findings demonstrate that caspase-11/GSDMD-dependent NETs promote renal fibrosis by facilitating inflammation and MMT, therefore highlighting the role and mechanisms of NETs in renal fibrosis.

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Neutrophil extracellular traps promote scar formation in post-epidural fibrosis

Cited by 24 publications

References 45 publications

Extracellular traps formation following cervical spinal cord injury

Extracellular traps formation following cervical spinal cord injury

Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension

GSDMD-dependent neutrophil extracellular traps promote macrophage-to-myofibroblast transition and renal fibrosis in obstructive nephropathy

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