neutrophil extracellular traps
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2023 ◽  
Vol 83 ◽  
Author(s):  
L.F.A. Diniz ◽  
B.K. Matsuba ◽  
P.S.S. Souza ◽  
B.R.P. Lopes ◽  
L.H. Kubo ◽  
...  

Abstract The human respiratory syncytial virus (hRSV) is the most common cause of severe lower respiratory tract diseases in young children worldwide, leading to a high number of hospitalizations and significant expenditures for health systems. Neutrophils are massively recruited to the lung tissue of patients with acute respiratory diseases. At the infection site, they release neutrophil extracellular traps (NETs) that can capture and/or inactivate different types of microorganisms, including viruses. Evidence has shown that the accumulation of NETs results in direct cytotoxic effects on endothelial and epithelial cells. Neutrophils stimulated by the hRSV-F protein generate NETs that are able to capture hRSV particles, thus reducing their transmission. However, the massive production of NETs obstructs the airways and increases disease severity. Therefore, further knowledge about the effects of NETs during hRSV infections is essential for the development of new specific and effective treatments. This study evaluated the effects of NETs on the previous or posterior contact with hRSV-infected Hep-2 cells. Hep-2 cells were infected with different hRSV multiplicity of infection (MOI 0.5 or 1.0), either before or after incubation with NETs (0.5–16 μg/mL). Infected and untreated cells showed decreased cellular viability and intense staining with trypan blue, which was accompanied by the formation of many large syncytia. Previous contact between NETs and cells did not result in a protective effect. Cells in monolayers showed a reduced number and area of syncytia, but cell death was similar in infected and non-treated cells. The addition of NETs to infected tissues maintained a similar virus-induced cell death rate and an increased syncytial area, indicating cytotoxic and deleterious damages. Our results corroborate previously reported findings that NETs contribute to the immunopathology developed by patients infected with hRSV.


2022 ◽  
Vol 12 ◽  
Author(s):  
Qi You ◽  
Yiming Shen ◽  
Yiling Wu ◽  
Yuyan Li ◽  
Chang Liu ◽  
...  

Increased formation of neutrophil extracellular traps (NETs) is associated with gut leakage in type 1 diabetes (T1D). To explore the mechanism of how enteropathy exacerbated by NETs triggers pancreatic autoimmunity in T1D, we carried out a correlation analysis for NET formation with gut barrier functions and autoimmunity in nonobese diabetic (NOD) mice. Inducing chronic colitis or knocking out of peptidyl arginine deiminase type 4 (PAD4) in NOD mice were used to further study the effect of NET formation on the progression of T1D. Microbial alterations in Deferribacteres and Proteobacteria, along with the loss of gut barrier function, were found to be associated with increased endotoxin and abnormal formation of NETs in NOD mice. Both DSS-induced colitis and knockout of PAD4 in NOD mice indicated that PAD4-dependent NET formation was involved in the aggravation of gut barrier dysfunction, the production of autoantibodies, and the activation of enteric autoimmune T cells, which then migrated to pancreatic lymph nodes (PLNs) and caused self-damage. The current study thus provides evidence that PAD4-dependent NET formation is engaged in leaky gut triggering pancreatic autoimmunity and suggests that either degradation of NETs or inhibition of NET formation may be helpful for innovative therapeutic interventions in T1D.


Blood ◽  
2022 ◽  
Author(s):  
Evelien G.G. Sprenkeler ◽  
Anton T.J. Tool ◽  
Stefanie Henriet ◽  
Robin van Bruggen ◽  
Taco W. Kuijpers

Neutrophils are important effector cells in the host defense against invading micro-organisms. One of the mechanisms they employ to eliminate pathogens is the release of neutrophil extracellular traps (NETs). Although NET release and subsequent cell death known as NETosis have been intensively studied, the cellular components and factors determining or facilitating the formation of NETs remain incompletely understood. Using various actin polymerization and myosin II modulators on neutrophils from healthy individuals, we show that intact F-actin dynamics and myosin II function are essential for NET formation when induced by different stimuli, i.e. phorbol 12-myristate 13-acetate, monosodium urate crystals and Candida albicans. The role of actin polymerization in NET formation could not be explained by the lack of reactive oxygen species production or granule release, which were normal or enhanced under the given conditions. Neutrophils from patients with very rare inherited actin polymerization defects by either ARPC1B- or MKL1-deficiency also failed to show NETosis. We found that upon inhibition of actin dynamics there is a lack of translocation of NE to the nucleus, which may well explain the impaired NET formation. Collectively, our data illustrate the essential requirement of an intact and active actin polymerization process, as well as active myosin II to enable the release of nuclear DNA by neutrophils during NET formation.


2022 ◽  
Author(s):  
Arisa Senda ◽  
Ryutaro Sasai ◽  
Kurumi Kato ◽  
Yuka Nishibata ◽  
Sakiko Masuda ◽  
...  

AbstractSystemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are autoimmune diseases that often cause rapidly progressive glomerulonephritis, with neutrophil extracellular traps (NETs) involved in their pathogenesis. However, the involvement of NETs in the renal damage caused by SLE/AAV overlap syndrome has not been clarified yet. In this study, we detected renal deposition of NETs in a patient with SLE/AAV overlap syndrome. In addition, a significantly increased level of NET-inducing activity was observed in the patient’s serum, which improved with treatment. On the other hand, a markedly lower level of NET degradation was observed in the patient’s serum as compared to healthy subjects’ sera, without any posttreatment changes. These findings suggest that NETs may play a role in the pathogenesis of renal injury associated with SLE/AAV overlap syndrome.


Author(s):  
Rahul Kumar ◽  
Vijay K. Sonkar ◽  
Jagadish Swamy ◽  
Azaj Ahmed ◽  
Anjali A. Sharathkumar ◽  
...  

Background Human aging is associated with increased risk of thrombosis, but the mechanisms are poorly defined. We hypothesized that aging induces peroxide‐dependent release of neutrophil extracellular traps that contribute to thrombin generation and thrombosis. Methods and Results We studied C57BL6J mice and littermates of glutathione peroxidase‐1 transgenic and wild‐type mice at young (4 month) and old (20 month) ages and a healthy cohort of young (18–39 years) or middle‐aged/older (50–72 years) humans. In plasma, we measured thrombin generation potential and components of neutrophil extracellular traps (cell‐free DNA and citrullinated histone). Aged wild‐type mice displayed a significant increase in thrombin generation that was decreased in aged glutathione peroxidase‐1 transgenic mice. Both aged wild‐type and aged glutathione peroxidase‐1 transgenic mice demonstrated similar elevation of plasma cell‐free DNA compared with young mice. In contrast, plasma levels of citrullinated histone were not altered with age or genotype. Release of neutrophil extracellular traps from neutrophils in vitro was also similar between young and aged wild‐type or glutathione peroxidase‐1 transgenic mice. Treatment of plasma or mice with DNase 1 decreased age‐associated increases in thrombin generation, and DNase 1 treatment blocked the development of experimental venous thrombi in aged C57BL6J mice. Similarly, thrombin generation potential and plasma cell‐free DNA, but not citrullinated histone, were higher in middle‐aged/older humans, and treatment of plasma with DNase 1 reversed the increase in thrombin generation. Conclusions We conclude that DNase 1 limits thrombin generation and protects from venous thrombosis during aging, likely by hydrolyzing cell‐free DNA.


Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 236
Author(s):  
Evelien G. G. Sprenkeler ◽  
Judith Zandstra ◽  
Nadine D. van Kleef ◽  
Ines Goetschalckx ◽  
Bibian Verstegen ◽  
...  

Neutrophils are the most abundant innate immune cells in the circulation and they are the first cells recruited to sites of infection or inflammation. Almost half of the intracellular protein content in neutrophils consists of S100A8 and S100A9, though there has been controversy about their actual localization. Once released extracellularly, these proteins are thought to act as damage-associated molecular patterns (DAMPs), though their mechanism of action is not well understood. These S100 proteins mainly form heterodimers (S100A8/A9, also known as calprotectin) and this heterocomplex is recognized as a useful biomarker for several inflammatory diseases. We observed that S100A8/A9 is highly present in the cytoplasmic fraction of neutrophils and is not part of the granule content. Furthermore, we found that S100A8/A9 was not released in parallel with granular content but upon the formation of neutrophil extracellular traps (NETs). Accordingly, neutrophils of patients with chronic granulomatous disease, who are deficient in phorbol 12-myristate 13-acetate (PMA)-induced NETosis, did not release S100A8/A9 upon PMA stimulation. Moreover, we purified S100A8/A9 from the cytoplasmic fraction of neutrophils and found that S100A8/A9 could induce neutrophil activation, including adhesion and CD11b upregulation, indicating that this DAMP might amplify neutrophil activation.


2022 ◽  
Vol 2022 ◽  
pp. 1-11
Author(s):  
Lemeng Zhang ◽  
Huifang Yi ◽  
Jianhua Chen ◽  
Haitao Li ◽  
Yongzhong Luo ◽  
...  

Introduction. The biological functions of neutrophil extracellular traps (NETs) in tumorigenesis have drawn an increasing amount of attention. This study explored the relationship between NETs and the inflammatory microenvironment in lung cancer cell invasion and metastasis. Methods. NETs were quantified using myeloperoxidase (MPO–DNA) and immunofluorescence staining. Cytokine levels were measured using ELISA kits. THP-1 and A549 cells were used for in vitro experiments. Transwell and Matrigel assays were used to assess the invasion and migration abilities of the cells. Results. Neutrophil infiltration and NET formation were observed in the lung cancer tissues. Compared with healthy controls, the level of MPO–DNA complexes in lung cancer patients increased remarkably and was positively correlated with peripheral blood neutrophil counts, smoking status, and poor prognosis. Increased circulating NET levels were also positively correlated with the levels of inflammatory cytokines, including IL-1β, IL-6, IL-18, and TNF-α. Neutrophils isolated from patients with lung cancer are more prone to NET release. NETs can promote the invasion and migration ability of THP-1 and A549 cell in coculture systems, while pretreatment with NET inhibitors can effectively reduce NET-induced invasion and metastasis. The ability of NETs to promote invasion and metastasis is partly dependent on macrophages. Conclusion. Taken together, our study demonstrated that NETs facilitate A549 cell invasion and migration in a macrophage-maintained inflammatory microenvironment.


Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 191
Author(s):  
Apurwa Singhal ◽  
Shubhi Yadav ◽  
Tulika Chandra ◽  
Shrikant R. Mulay ◽  
Anil Nilkanth Gaikwad ◽  
...  

Neutrophil extracellular traps (NETs) are associated with multiple disease pathologies including sepsis, asthma, rheumatoid arthritis, cancer, systemic lupus erythematosus, acute respiratory distress syndrome, and COVID-19. NETs, being a disintegrated death form, suffered inconsistency in their identification, nomenclature, and quantifications that hindered therapeutic approaches using NETs as a target. Multiple strategies including microscopy, ELISA, immunoblotting, flow cytometry, and image-stream-based methods have exhibited drawbacks such as being subjective, non-specific, error-prone, and not being high throughput, and thus demand the development of innovative and efficient approaches for their analyses. Here, we established an imaging and computational algorithm using high content screening (HCS)—cellomics platform that aid in easy, rapid, and specific detection as well as analyses of NETs. This method employed membrane-permeable and impermeable DNA dyes in situ to identify NET-forming cells. Automated algorithm-driven single-cell analysis of change in nuclear morphology, increase in nuclear area, and change in intensities provided precise detection of NET-forming cells and eliminated user bias with other cell death modalities. Further combination with Annexin V staining in situ detected specific death pathway, e.g., apoptosis, and thus, discriminated between NETs, apoptosis, and necrosis. Our approach does not utilize fixation and permeabilization steps that disturb NETs, and thus, allows the time-dependent monitoring of NETs. Together, this specific imaging-based high throughput method for NETs analyses may provide a good platform for the discovery of potential inhibitors of NET formation and/or agents to modulate neutrophil death, e.g., NETosis-apoptosis switch, as an alternative strategy to enhance the resolution of inflammation.


2022 ◽  
pp. 108516
Author(s):  
Hayder M. Al-Kuraishy ◽  
Ali I. Al-Gareeb ◽  
Hany Akeel Al-hussaniy ◽  
Nasser A. Hadi Al-Harcan ◽  
Athanasios Alexiou ◽  
...  

Lab on a Chip ◽  
2022 ◽  
Author(s):  
Miyuki Sakuma ◽  
Xiao Wang ◽  
Felix Ellett ◽  
Jon F. Edd ◽  
Babatunde Kehinde ◽  
...  

Neutrophils are the largest population of white blood cells in the circulation, and their primary function is to protect the body from microbes. They can release the chromatin in their...


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