scholarly journals S100A8/A9 Is a Marker for the Release of Neutrophil Extracellular Traps and Induces Neutrophil Activation

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 236
Author(s):  
Evelien G. G. Sprenkeler ◽  
Judith Zandstra ◽  
Nadine D. van Kleef ◽  
Ines Goetschalckx ◽  
Bibian Verstegen ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Activation ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Intracellular Protein ◽  
Cytoplasmic Fraction ◽  
Extracellular Traps ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

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.

Natural Killer Cells Induce the Formation of Neutrophil Extracellular Traps (NETs) in Venous Thrombosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1424-1424
Author(s):  
François-René Bertin ◽  
Sandrine Laurance ◽  
Catherine Lemarie ◽  
Mark Blostein
Keyword(s):  
Venous Thrombosis ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Flow Restriction ◽  
Extracellular Traps

Abstract Thrombosis is considered to be a pathological deviation of physiologic hemostasis involving similar mechanisms. Interestingly, recent work demonstrates that innate immune cells promote venous thrombosis. Innate immune cells were shown to collaborate to induce the activation of the coagulation cascade and platelets. In particular, neutrophils contribute to venous thrombosis through the release of neutrophil extracellular traps (NETs). However, the mechanism triggering the formation of NETs during venous thrombosis remain unknown. Of interest, a study showed that IFNγ induced the formation of NETs. Thus, we investigated the role of IFNγ-producing cells in the development of thrombosis. We used mice lacking IFNγ, Tbet (the transcription factor regulating the expression of IFNγ) or wild type mice. Venous thrombosis was induced using the flow restriction model in the inferior vena cava , as has been previously published. In Tbet-/-, IFNγ-/- and WT mice, we show that the absence of Tbet or IFNγ decreases the formation of thrombi after venous thrombosis induction, suggesting that the Tbet+/IFNγ producing cells are required for the early development of venous thrombosis. Comparing the composition of the thrombi from Tbet-/-, IFNγ-/- and WT mice, we show that, in all mice, neutrophils are the main cellular component of thrombi followed by monocytes; however, the number of neutrophil extracellular traps (NETs) formed during thrombosis is significantly lower in Tbet-/- and IFNγ-/- mice. Furthermore, NET formation is also decreased in WT mice specifically depleted of IFNγ and increases in Tbet-/- and IFNγ-/- mice injected with recombinant IFNγ. In vitro, we show that stimulation of WT murine neutrophils with recombinant IFNγ triggers the formation of NETs demonstrating that Tbet and IFNγ are crucial for NET formation by neutrophils. Natural killer (NK) cells are the main producers of IFNγ . Thus, we investigated the role of NK cells in venous thrombosis induced by flow restriction. NK cells were specifically depleted with an antibody during the development of venous thrombosis. The absence of NK cells results in smaller thrombi suggesting that NK cells are required for early thrombus development. Additionally, depletion in NK cells results in decreased in-situ IFNγ production and decreased NET formation. To directly link NK cells to the formation of NETs, WT neutrophils were co-cultured with Tbet-/- and IFNγ-/- NK cells. We show that WT neutrophils release less NETs when cultured with Tbet-/- and IFNγ-/- NK cells as compared to WT NK cells. These data suggest that NK cells trigger the formation of NETs by neutrophils through the production of IFNγ. Hence, we demonstrate that, in a partial flow restriction model of venous thrombosis, Tbet and IFNγ are crucial for thrombus development by promoting the formation of NETs by neutrophils and that NK cells are key effector cells in this process. Disclosures Blostein: boehringer-ingelheim: Research Funding.

scholarly journals Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

2020 ◽  
Vol 2020 ◽  
pp. 1-25 ◽  
Author(s):  
Sebastiano Cicco ◽  
Gerolamo Cicco ◽  
Vito Racanelli ◽  
Angelo Vacca
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Targeted Therapy ◽  
High Mobility ◽  
Neutrophil Extracellular Traps ◽  
Lung Cells ◽  
Extracellular Traps ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Excessive Inflammatory Response

COVID-19 is a pandemic disease caused by the new coronavirus SARS-CoV-2 that mostly affects the respiratory system. The consequent inflammation is not able to clear viruses. The persistent excessive inflammatory response can build up a clinical picture that is very difficult to manage and potentially fatal. Modulating the immune response plays a key role in fighting the disease. One of the main defence systems is the activation of neutrophils that release neutrophil extracellular traps (NETs) under the stimulus of autophagy. Various molecules can induce NETosis and autophagy; some potent activators are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). This molecule is released by damaged lung cells and can induce a robust innate immunity response. The increase in HMGB1 and NETosis could lead to sustained inflammation due to SARS-CoV-2 infection. Therefore, blocking these molecules might be useful in COVID-19 treatment and should be further studied in the context of targeted therapy.

scholarly journals NETosis occurs independently of neutrophil serine proteases

2020 ◽  
Vol 295 (51) ◽  
pp. 17624-17631
Author(s):  
Paulina Kasperkiewicz ◽  
Anne Hempel ◽  
Tomasz Janiszewski ◽  
Sonia Kołt ◽  
Scott J. Snipas ◽  
...  
Keyword(s):  
Immune Cells ◽  
Serine Proteases ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Chromatin Decondensation ◽  
Primary Host ◽  
Extracellular Traps ◽  
Cellular Dna ◽  
Specific Inhibitors

Neutrophils are primary host innate immune cells defending against pathogens. One proposed mechanism by which neutrophils prevent the spread of pathogens is NETosis, the extrusion of cellular DNA resulting in neutrophil extracellular traps (NETs). The protease neutrophil elastase (NE) has been implicated in the formation of NETs through proteolysis of nuclear proteins leading to chromatin decondensation. In addition to NE, neutrophils contain three other serine proteases that could compensate if the activity of NE was neutralized. However, whether they do play such a role is unknown. Thus, we deployed recently described specific inhibitors against all four of the neutrophil serine proteases (NSPs). Using specific antibodies to the NSPs along with our labeled inhibitors, we show that catalytic activity of these enzymes is not required for the formation of NETs. Moreover, the NSPs that decorate NETs are in an inactive conformation and thus cannot participate in further catalytic events. These results indicate that NSPs play no role in either NETosis or arming NETs with proteolytic activity.

scholarly journals A Review of the Neutrophil Extracellular Traps (NETs) from Cow, Sheep and Goat Models

2021 ◽  
Vol 22 (15) ◽  
pp. 8046
Author(s):  
Mulumebet Worku ◽  
Djaafar Rehrah ◽  
Hamid D. Ismail ◽  
Emmanuel Asiamah ◽  
Sarah Adjei-Fremah
Keyword(s):  
One Health ◽  
Inflammatory Diseases ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Response Mechanism ◽  
Global Food Security ◽  
Extracellular Traps ◽  
Definition Of ◽  
Global Food ◽  
Insight Into

This review provides insight into the importance of understanding NETosis in cows, sheep, and goats in light of the importance to their health, welfare and use as animal models. Neutrophils are essential to innate immunity, pathogen infection, and inflammatory diseases. The relevance of NETosis as a conserved innate immune response mechanism and the translational implications for public health are presented. Increased understanding of NETosis in ruminants will contribute to the prediction of pathologies and design of strategic interventions targeting NETs. This will help to control pathogens such as coronaviruses and inflammatory diseases such as mastitis that impact all mammals, including humans. Definition of unique attributes of NETosis in ruminants, in comparison to what has been observed in humans, has significant translational implications for one health and global food security, and thus warrants further study.

scholarly journals Neutrophil Extracellular Traps in the Establishment and Progression of Renal Diseases

Medicina ◽  
2019 ◽  
Vol 55 (8) ◽  
pp. 431 ◽  
Author(s):  
Hector Salazar-Gonzalez ◽  
Alexa Zepeda-Hernandez ◽  
Zesergio Melo ◽  
Diego Eduardo Saavedra-Mayorga ◽  
Raquel Echavarria
Keyword(s):  
Inflammatory Diseases ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Renal Diseases ◽  
Glomerular Injury ◽  
Kidney Fibrosis ◽  
Extracellular Traps ◽  
Autoimmune Processes ◽  
Pro Inflammatory Cytokines

Uncontrolled inflammatory and immune responses are often involved in the development of acute and chronic forms of renal injury. Neutrophils are innate immune cells recruited early to sites of inflammation, where they produce pro-inflammatory cytokines and release mesh-like structures comprised of DNA and granular proteins known as neutrophil extracellular traps (NETs). NETs are potentially toxic, contribute to glomerular injury, activate autoimmune processes, induce vascular damage, and promote kidney fibrosis. Evidence from multiple studies suggests that an imbalance between production and clearance of NETs is detrimental for renal health. Hence strategies aimed at modulating NET-associated processes could have a therapeutic impact on a myriad of inflammatory diseases that target the kidney. Here, we summarize the role of NETs in the pathogenesis of renal diseases and their mechanisms of tissue damage.

scholarly journals Neutrophil Extracellular Traps: As Antimicrobial Peptides

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Quratul Ann
Keyword(s):  
Blood Circulation ◽  
Immune Reaction ◽  
Inflammatory Diseases ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Neutrophil Extracellular Trap ◽  
Oxygen Species ◽  
Extracellular Traps ◽  
Response System ◽  
Infection And Inflammation

Neutrophils are an integral part of innate immune response system, abundantly present in blood circulation. They are the primary responders to the injury or intruding pathogens in human body. Neutrophils engulf infectious microorganisms by the process of phagocytosis, which usually initiates the production of reactive oxygen species and adhere the neutrophilic antimicrobial granules with vacuoles containing pathogens. Upon activation, neutrophils also render signals for stimulation and maturation of macrophages and dendritic cells. They release neutrophil extracellular traps for the suppression of infection and inflammation along with other antimicrobial molecules. The antimicrobials that are present in neutrophil extracellular traps not only eradicate microbes but also moderately contribute to the pathogenesis of various diseases such as destruction of tissue observed in periodontitis. Genetic shortcomings in neutrophils with respect to their chemotaxis, migration and phagocytosis become evident as severe forms of periodontitis, thus highlighting their role in innate immunity. Therefore, the present review is undertaken to highlight the importance of production and release of neutrophil extracellular trap in the regulation of immune reaction and its role in periodontal disease. A comprehensive database search was performed to gather all the relevant data related to the action of neutrophil and neutrophil extracellular traps in various inflammatory diseases with special emphasis on periodontitis.

Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs)

2021 ◽  
pp. 1575-1589
Author(s):  
Cameron G. McCarthy ◽  
Piu Saha ◽  
Rachel M. Golonka ◽  
Camilla F. Wenceslau ◽  
Bina Joe ◽  
...  
Keyword(s):  
Immune Cells ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Extracellular Traps

scholarly journals Orchestration of Neutrophil Extracellular Traps (Nets), a Unique Innate Immune Function during Chronic Obstructive Pulmonary Disease (COPD) Development

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 53
Author(s):  
Anjali Trivedi ◽  
Meraj A. Khan ◽  
Geetanjali Bade ◽  
Anjana Talwar
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Chronic Obstructive ◽  
Tissue Destruction ◽  
Mucus Production ◽  
Obstructive Pulmonary Disease ◽  
Extracellular Traps ◽  
Endothelial Cell Death

Morbidity, mortality and economic burden caused by chronic obstructive pulmonary disease (COPD) is a significant global concern. Surprisingly, COPD is already the third leading cause of death worldwide, something that WHO had not predicted to occur until 2030. It is characterized by persistent respiratory symptoms and airway limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles of gases. Neutrophil is one of the key infiltrated innate immune cells in the lung during the pathogenesis of COPD. Neutrophils during pathogenic attack or injury decide to undergo for a suicidal death by releasing decondensed chromatin entangled with antimicrobial peptides to trap and ensnare pathogens. Casting neutrophil extracellular traps (NETs) has been widely demonstrated to be an effective mechanism against invading microorganisms thus controlling overwhelming infections. However, aberrant and massive NETs formation has been reported in several pulmonary diseases, including chronic obstructive pulmonary disease. Moreover, NETs can directly induce epithelial and endothelial cell death resulting in impairing pulmonary function and accelerating the progression of the disease. Therefore, understanding the regulatory mechanism of NET formation is the need of the hour in order to use NETs for beneficial purpose and controlling their involvement in disease exacerbation. For example, DNA neutralization of NET proteins using protease inhibitors and disintegration with recombinant human DNase would be helpful in controlling excess NETs. Targeting CXC chemokine receptor 2 (CXCR2) would also reduce neutrophilic inflammation, mucus production and neutrophil-proteinase mediated tissue destruction in lung. In this review, we discuss the interplay of NETs in the development and pathophysiology of COPD and how these NETs associated therapies could be leveraged to disrupt NETopathic inflammation as observed in COPD, for better management of the disease.

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