TLR3 Regulated Poly I:C-Induced Neutrophil Extracellular Traps and Acute Lung Injury Partly Through p38 MAP Kinase

Gan, Tingting; Yang, Yonglin; Hu, Fan; Chen, Xichen; Zhou, Jiawei; Li, Yan; Xü, Ying; Wang, Huijuan; Chen, Yu; Zhang, Mingshun

doi:10.3389/fmicb.2018.03174

Cited by 49 publications

(48 citation statements)

References 54 publications

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“…We demonstrated markedly elevated baseline NET levels in PMNs isolated from COVID-19 patients, whereas PMNs isolated from healthy adults remained unaltered under basal conditions ( P = .0012; Figure 2B-C ). We also demonstrated that PMA, a nonphysiologic agonist, induced NETs in vitro by PMNs isolated from healthy adults, as previously reported, 23 but failed to further increase NET formation over the already high baseline in COVID-19 PMNs ( Figure 2B-C ). Although PMNs do not express Toll-like receptor 3 (TLR3), 24 , 25 we also found that poly(I:C), a damage-associated molecular pattern that typically signals through TLR3, induces NETs in PMNs isolated from COVID-19 adults and healthy donors (supplemental Figure 3).…”

Section: Resultssupporting

confidence: 90%

Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Middleton

Denorme³

et al. 2020

Blood

1,197

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COVID-19 affects millions of patients worldwide with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens and can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n=33) with age- and sex-matched controls (n=17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), Platelet Factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-Inhibitory Factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19 with intubation (P<0.0001) and death as outcome (P<0.0005). Illness severity correlated directly with plasma MPO-DNA complexes (P=0.0360), while PaO2/FiO2 correlated inversely(P=0.0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19 and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline and COVID-19 plasma triggered NET formation which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19 and NETs may represent targets for therapeutic intervention.

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Section: Resultssupporting

confidence: 90%

Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Middleton

Denorme³

et al. 2020

Blood

1,197

1,390

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“…In various disease models, DNase effectively degraded NETs and antagonized the effects of NETs 34 , 35 . A mouse model of laminectomy was established, and gross observation revealed that the scar formation was reduced in the mice treated with DNase I 30 days post operation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The powder of DNase I was diluted with physiological saline to 1 mg/ml, and the dosage for each mouse was 5 mg/kg (ref. 34 ). The diluted solution was absorbed with a gelatin sponge matching the size of the wound, and it was placed on the wound and then sutured.…”

Section: Methodsmentioning

confidence: 99%

Neutrophil extracellular traps promote scar formation in post-epidural fibrosis

et al. 2020

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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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“…In the present study, DNase alleviated BPD disease severity. A DNA backbone served as a scaffold for NETs; DNase degraded DNA and therefore diminished the functions of NETs 41 . DNase, which has been clinically approved for the treatment of cystic fibrosis 42 , warrants further examination in BPD therapy.…”

Section: Discussionmentioning

confidence: 99%

IL-33-induced neutrophil extracellular traps degrade fibronectin in a murine model of bronchopulmonary dysplasia

Jin

Gao

et al. 2020

Cell Death Discov.

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Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in preterm neonates. Extracellular matrix (ECM) abnormalities reshape lung development, contributing to BPD progression. In the present study, we first discovered that the ECM component fibronectin was reduced in the pulmonary tissues of model mice with BPD induced by lipopolysaccharide (LPS) and hyper-oxygen. Meanwhile, interleukin-33 (IL-33) and other inflammatory cytokines were elevated in BPD lung tissues. LPS stimulated the production of IL-33 in alveolar epithelial cells via myeloid differentiation factor 88 (MyD88), protein 38 (p38), and nuclear factor-kappa B (NF-κB) protein 65 (p65). Following the knockout of either IL-33 or its receptor suppression of tumorigenicity 2 (ST2) in mice, BPD disease severity was improved, accompanied by elevated fibronectin. ST2 neutralization antibody also relieved BPD progression and restored the expression of fibronectin. IL-33 induced the formation of neutrophil extracellular traps (NETs), which degraded fibronectin in alveolar epithelial cells. Moreover, DNase-mediated degradation of NETs was protective against BPD. Finally, a fibronectin inhibitor directly decreased fibronectin and caused BPD-like disease in the mouse model. Our findings may shed light on the roles of IL-33-induced NETs and reduced fibronectin in the pathogenesis of BPD.

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TLR3 Regulated Poly I:C-Induced Neutrophil Extracellular Traps and Acute Lung Injury Partly Through p38 MAP Kinase

Cited by 49 publications

References 54 publications

Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Neutrophil extracellular traps promote scar formation in post-epidural fibrosis

IL-33-induced neutrophil extracellular traps degrade fibronectin in a murine model of bronchopulmonary dysplasia

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