scholarly journals Neutrophil extracellular traps and inflammasomes cooperatively promote venous thrombosis in mice

2021 ◽  
Vol 5 (9) ◽  
pp. 2319-2324
Author(s):  
Joana Campos ◽  
Tatyana Ponomaryov ◽  
Alexandra De Prendergast ◽  
Katharine Whitworth ◽  
Christopher W. Smith ◽  
...  
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Simultaneous Formation ◽  
Vein Thrombosis ◽  
Extracellular Traps ◽  
Caspase 1 ◽  
Histone 3 ◽  
Adhesive Surface ◽  
Deep Vein ◽  
Active Caspase

Abstract Deep vein thrombosis (DVT) is linked to local inflammation. A role for both neutrophil extracellular traps (NETs) and the assembly of inflammasomes (leading to caspase-1–dependent interleukin-1β activation) in the development of DVT was recently suggested. However, no link between these 2 processes in the setting of thrombosis has been investigated. Here, we demonstrate that stimulation of neutrophils induced simultaneous formation of NETs and active caspase-1. Caspase-1 was largely associated with NETs, suggesting that secreted active caspase-1 requires NETs as an adhesive surface. NETs and their components, histones, promoted robust caspase-1 activation in platelets with the strongest effect exerted by histones 3/4. Murine DVT thrombi contained active caspase-1, which peaked at 6 hours when compared with 48-hour thrombi. Platelets constituted more than one-half of cells containing active caspase-1 in dissociated thrombi. Using intravital microscopy, we identified colocalized NETs and caspase-1 as well as platelet recruitment at the site of thrombosis. Pharmacological inhibition of caspase-1 strongly reduced DVT in mice, and thrombi that still formed contained no citrullinated histone 3, a marker of NETs. Taken together, these data demonstrate a cross-talk between NETs and inflammasomes both in vitro and in the DVT setting. This may be an important mechanism supporting thrombosis in veins.

scholarly journals Neutrophil Extracellular Traps in Arterial and Venous Thrombosis

2019 ◽  
Vol 45 (01) ◽  
pp. 086-093 ◽  
Author(s):  
Elodie Laridan ◽  
Kimberly Martinod ◽  
Simon De Meyer
Keyword(s):  
Myocardial Infarction ◽  
Thrombus Formation ◽  
Neutrophil Extracellular Traps ◽  
Major Health ◽  
Vein Thrombosis ◽  
Extracellular Traps ◽  
Thrombotic Complications ◽  
Decondensed Chromatin ◽  
Deep Vein ◽  
Novel Therapeutic

AbstractThrombotic complications are still a major health risk worldwide. Our view on the pathophysiology of thrombosis has significantly changed since the discovery of neutrophil extracellular traps (NETs) and their prothrombotic characteristics. Generated by neutrophils that release their decondensed chromatin as a network of extracellular fibers, NETs promote thrombus formation by serving as a scaffold that activates platelets and coagulation. The thrombogenic involvement of NETs has been described in various settings of thrombosis, including stroke, myocardial infarction, and deep vein thrombosis. The aim of this review is to summarize existing evidence showing the presence of NETs in human thrombus material. Following an introduction on NETs and their role in thrombus formation, the authors address studies showing the presence of NETs in arterial or venous thrombi. In addition, they focus on potential novel therapeutic opportunities to resolve or prevent thrombosis by targeting NETs.

scholarly journals Neutralizing the pathological effects of extracellular histones with small polyanions

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Connor H. O’ Meara ◽  
Lucy A. Coupland ◽  
Farzaneh Kordbacheh ◽  
Benjamin J. C. Quah ◽  
Chih-Wei Chang ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Vein Thrombosis ◽  
Extracellular Traps ◽  
Extracellular Histones ◽  
Tissue Flap ◽  
Deep Vein

AbstractExtracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small polyanions (SPAs) (~0.9–1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.

scholarly journals Neutrophil extracellular traps promote deep vein thrombosis in mice

2012 ◽  
Vol 10 (1) ◽  
pp. 136-144 ◽  
Author(s):  
A. BRILL ◽  
T. A. FUCHS ◽  
A. S. SAVCHENKO ◽  
G. M. THOMAS ◽  
K. MARTINOD ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Neutrophil Extracellular Traps ◽  
Vein Thrombosis ◽  
Extracellular Traps ◽  
Deep Vein

scholarly journals Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Mitchell R. Dyer ◽  
Qiwei Chen ◽  
Shannon Haldeman ◽  
Hamza Yazdani ◽  
Rosemary Hoffman ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Neutrophil Extracellular Traps ◽  
Vein Thrombosis ◽  
Extracellular Traps ◽  
Deep Vein

scholarly journals Neutrophil extracellular traps induce MCP-1 release from endothelial cells at the plaque rupture site in acute myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Ondracek ◽  
T.M Hofbauer ◽  
A Mangold ◽  
T Scherz ◽  
V Seidl ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Endothelial Cells ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Coronary Intervention ◽  
Neutrophil Extracellular Traps ◽  
Funding Source ◽  
Extracellular Traps

Abstract Introduction Leukocyte-mediated inflammation is crucial in acute myocardial infarction (AMI). We recently observed that neutrophil extracellular traps (NETs) are increased at the culprit site, promoting activation and differentiation of fibrocytes, cells with mesenchymal and leukocytic properties. Fibrocyte migration is mediated by monocyte chemoattractant protein (MCP)-1 and C-C chemokine receptor type 2 (CCR2). We investigated the interplay between NETs, fibrocyte function, and MCP-1 in AMI. Methods Culprit site and femoral blood of AMI patients was drawn during percutaneous coronary intervention. We characterized CCR2 expression of fibrocytes by flow cytometry. MCP-1 and the NET marker citrullinated histone H3 (citH3) were measured by ELISA. Fibrocytes were treated in vitro with MCP-1. Human coronary arterial endothelial cells (hCAECs) were stimulated with isolated NETs, and MCP-1 was measured by ELISA and qPCR. The influence of MCP-1 on NET formation in vitro was assessed using isolated neutrophils. Results We have included 50 consecutive AMI patients into the study. NETs and concentrations of MCP-1 were increased at the CLS. NET stimulation of hCAECs induced MCP-1 on mRNA and protein level. Increasing MCP-1 gradient was associated with fibrocyte accumulation at the site of occlusion. In the presence of higher MCP-1 these fibrocytes expressed proportionally less CCR2 than peripheral fibrocytes. In vitro, MCP-1 dose-dependently decreased fibrocyte CCR2 and reduced ex vivo NET release of healthy donor neutrophils. Conclusions NETs induce endothelial MCP-1 release, presumably promoting a chemotactic gradient for leukocyte and fibrocyte migration. MCP-1 mediated inhibition of NET formation could point to a negative feedback loop. These data will shed light on vascular healing. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund

755 CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A803-A803 ◽  
Author(s):  
Alvaro Teijeira ◽  
Saray Garasa ◽  
Itziar Migueliz ◽  
Assunta Cirella ◽  
Ignacio Melero
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Mouse Models ◽  
Chemokine Receptor ◽  
Suppressor Cells ◽  
Neutrophil Extracellular Traps ◽  
Myeloid Derived Suppressor Cells ◽  
Extracellular Traps ◽  
Tumor Associated Neutrophils

BackgroundNeutrophils are expanded and abundant in an important fraction (up to 35% of patients) in cancer-bearing hosts. When neutrophils are expanded, they usually promote exert immunomodulatory functions promoting tumor progression and the generation of metastases. Neutrophils can undergo a specialized form of cell death called NETosis that is characterized by the extrusion of their DNA to contain infections. In cancer NETs have been described to promote metastases in mouse models. IL-8, a CXCR1/2 ligand clinically targeted by blocking antibodies, has been described to induce NETosis and is upregulated in many cancer patients. Our hypothesis is that chemokines secreted by cancer cells can mediate NETosis in tumor associated neutrophils and that NETs can be one of the immunomodulatory mechanisms provided by tumor associated neutrophils.MethodsNETosis induction of peripheral neutrophils and granulocytic myeloid derived suppressor cells by different chemotactic stimuli, tumor cell supernatants and cocultures upon CXCR1/2 blockade. NET immunodetection in mouse models and xenograft tumors upon CXCR1/2 blockade. In vitro tumor cytotoxicity assays in the presence/absence of NETs, and videomicroscopy studies in vitro and by intravital imaging to test NETs inhibition of immune cytotoxicity by immune-cell/target-cell inhibition. Tumor growth studies and metastases models in the presence of NETosis inhibitors and in combination with checkpoint blockade in mouse cancer models.ResultsUnder the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.ConclusionsCXCR1 and 2 are the main receptors mediating NETosis of tumor associated neutrophils in our in-vitro and in vivo systems expressing high levels of CXCR1 and 2 ligands. NETs limit cancer cell cytotoxicity by impeding contacts with cancer cells.

scholarly journals Neutrophil Extracellular Traps Serve as Key Effector Molecules in the Protection Against Phialophora verrucosa

2021 ◽  
Vol 186 (3) ◽  
pp. 367-375
Author(s):  
Qin Liu ◽  
Wenjuan Yi ◽  
Si Jiang ◽  
Jiquan Song ◽  
Pin Liang
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Immune Effector ◽  
Phialophora Verrucosa ◽  
Extracellular Traps ◽  
Sytox Green ◽  
Innate Immune Effector ◽  
Pathogen Control ◽  
Extracellular Structures

AbstractPhialophora verrucosa (P. verrucosa) is a pathogen that can cause chromoblastomycosis and phaeohyphomycosis. Recent evidence suggests that neutrophils can produce neutrophil extracellular traps (NETs) that can protect against invasive pathogens. As such, we herein explored the in vitro functional importance of P. verrucosa-induced NET formation. By assessing the co-localization of neutrophil elastase and DNA, we were able to confirm the formation of classical NETs entrapping P. verrucosa specimens. Sytox Green was then used to stain these NETs following neutrophil infection with P. verrucosa in order to quantify the formation of these extracellular structures. NET formation was induced upon neutrophil exposure to both live, UV-inactivated, and dead P. verrucosa fungi. The ability of these NETs to kill fungal hyphae and conidia was demonstrated through MTT and pouring plate assays, respectively. Overall, our results confirmed that P. verrucosa was able to trigger the production of NETs, suggesting that these extracellular structures may represent an important innate immune effector mechanism controlling physiological responses to P. verrucosa infection, thereby aiding in pathogen control during the acute phases of infection.

scholarly journals The state of art of neutrophil extracellular traps in protozoan and helminthic infections

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
César Díaz-Godínez ◽  
Julio C. Carrero
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Parasitic Infections ◽  
Parasitic Diseases ◽  
Helminth Parasites ◽  
Extracellular Traps ◽  
Helminthic Infections ◽  
Bacteria And Fungi ◽  
Net Release

AbstractNeutrophil extracellular traps (NETs) are DNA fibers associated with histones, enzymes from neutrophil granules and anti-microbial peptides. NETs are released in a process denominated NETosis, which involves sequential steps that culminate with the DNA extrusion. NETosis has been described as a new mechanism of innate immunity related to defense against different pathogens. The initial studies of NETs were carried out with bacteria and fungi, but currently a large variety of microorganisms capable of inducing NETs have been described including protozoan and helminth parasites. Nevertheless, we have little knowledge about how NETosis process is carried out in response to the parasites, and about its implication in the resolution of this kind of disease. In the best case, the NETs entrap and kill parasites in vitro, but in others, immobilize the parasites without affecting their viability. Moreover, insufficient studies on the NETs in animal models of infections that would help to define their role, and the association of NETs with chronic inflammatory pathologies such as those occurring in several parasitic infections have left open the possibility of NETs contributing to pathology instead of protection. In this review, we focus on the reported mechanisms that lead to NET release by protozoan and helminth parasites and the evidence that support the role of NETosis in the resolution or pathogenesis of parasitic diseases.

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