Netting Liver Disease: Neutrophil Extracellular Traps in the Initiation and Exacerbation of Liver Pathology

AbstractThe liver plays a vital role in the immune system. Its unique position in the portal circulation and the architecture of the hepatic sinusoids, in combination with the wide-ranged population of immunocompetent cells, make the liver function as an immune filter. To aid in pathogen clearance, once challenged, the liver initiates the rapid recruitment of a wide variety of inflammatory cells, including neutrophils. These neutrophils, in conjunction with platelets, facilitate the release of neutrophil extracellular traps (NETs), which are web-like structures of decondensed nuclear DNA, histones, and neutrophil proteins. NETs function as both a physical and a chemical barrier, binding and killing pathogens circulating in the blood stream. In addition to their antimicrobial role, NETs also bind platelets, activate coagulation, and exacerbate host inflammatory response. This interplay between inflammation and coagulation drives microvascular occlusion, ischemia, and (sterile) damage in liver disease. Although direct clinical evidence of this interplay is scarce, preliminary studies indicate that NETs contribute to progression of liver disease and (thrombotic) complications. Here, we provide an overview of the pathological mechanisms of NETs in liver disease. In addition, we summarize clinical evidence for NETs in different disease etiologies and complications of liver disease and discuss the possible implications for the use of NETs as a diagnostic marker and a therapeutic target in liver disease.

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The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.786387 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yilu Zhou ◽

Weimin Tao ◽

Fuyi Shen ◽

Weijia Du ◽

Zhendong Xu ◽

...

Keyword(s):

Current Knowledge ◽

Neutrophil Extracellular Traps ◽

Vital Role ◽

Extracellular Traps ◽

Protein Components ◽

Cancer Associated Thrombosis ◽

Coagulation Pathway

Neutrophils play a vital role in the formation of arterial, venous and cancer-related thrombosis. Recent studies have shown that in a process known as NETosis, neutrophils release proteins and enzymes complexed to DNA fibers, collectively called neutrophil extracellular traps (NETs). Although NETs were originally described as a way for the host to capture and kill bacteria, current knowledge indicates that NETs also play an important role in thrombosis. According to recent studies, the destruction of vascular microenvironmental homeostasis and excessive NET formation lead to pathological thrombosis. In vitro experiments have found that NETs provide skeletal support for platelets, red blood cells and procoagulant molecules to promote thrombosis. The protein components contained in NETs activate the endogenous coagulation pathway to promote thrombosis. Therefore, NETs play an important role in the formation of arterial thrombosis, venous thrombosis and cancer-related thrombosis. This review will systematically summarize and explain the study of NETs in thrombosis in animal models and in vivo experiments to provide new targets for thrombosis prevention and treatment.

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Formation of neutrophil extracellular traps requires actin cytoskeleton rearrangements

Blood ◽

10.1182/blood.2021013565 ◽

2022 ◽

Author(s):

Evelien G.G. Sprenkeler ◽

Anton T.J. Tool ◽

Stefanie Henriet ◽

Robin van Bruggen ◽

Taco W. Kuijpers

Keyword(s):

Actin Polymerization ◽

Nuclear Dna ◽

Myosin Ii ◽

Neutrophil Extracellular Traps ◽

Actin Dynamics ◽

Polymerization Process ◽

Effector Cells ◽

Extracellular Traps ◽

Cytoskeleton Rearrangements ◽

Cellular Components

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.

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Targeting neutrophil extracellular traps in severe acute pancreatitis treatment

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820974913 ◽

2020 ◽

Vol 13 ◽

pp. 175628482097491

Author(s):

Jing Hu ◽

Hongxin Kang ◽

Huan Chen ◽

Jiaqi Yao ◽

Xiaolin Yi ◽

...

Keyword(s):

Acute Pancreatitis ◽

Severe Acute Pancreatitis ◽

Inflammatory Cells ◽

Neutrophil Extracellular Traps ◽

Multiple Organ ◽

Organ Injury ◽

Normal Tissues ◽

Pathogen Invasion ◽

Extracellular Traps ◽

Abdominal Disease

Severe acute pancreatitis (SAP) is a critical abdominal disease associated with high death rates. A systemic inflammatory response promotes disease progression, resulting in multiple organ dysfunction. The functions of neutrophils in the pathology of SAP have been presumed traditionally to be activation of chemokine and cytokine cascades accompanying the inflammatory process. Recently, since their discovery, a new type of antimicrobial mechanism, neutrophil extracellular traps (NETs), and their role in SAP, has attracted widespread attention from the scientific community. Significantly different from phagocytosis and degranulation, NETs kill extracellular microorganisms by releasing DNA fibers decorated with granular proteins. In addition to their strong antimicrobial functions, NETs participate in the pathophysiological process of many noninfectious diseases. In SAP, NETs injure normal tissues under inflammatory stress, which is associated with the activation of inflammatory cells, to cause an inflammatory cascade, and SAP products also trigger NET formation. Thus, due to the interaction between NET generation and SAP, a treatment targeting NETs might become a key point in SAP therapy. In this review, we summarize the mechanism of NETs in protecting the host from pathogen invasion, the stimulus that triggers NET formation, organ injury associated with SAP involving NETs, methods to interrupt the harmful effects of NETs, and different therapeutic strategies to preserve the organ function of patients with SAP by targeting NETs.

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How Neutrophil Extracellular Traps Become Visible

Journal of Immunology Research ◽

10.1155/2016/4604713 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 47

Author(s):

Nicole de Buhr ◽

Maren von Köckritz-Blickwede

Keyword(s):

Electron Microscopy ◽

Nuclear Dna ◽

Defense Mechanism ◽

Neutrophil Extracellular Traps ◽

Immune Defense ◽

Extracellular Traps ◽

Activated Neutrophils ◽

Microscopy Techniques

Neutrophil extracellular traps (NETs) have been identified as a fundamental innate immune defense mechanism against different pathogens. NETs are characterized as released nuclear DNA associated with histones and granule proteins, which form an extracellular web-like structure that is able to entrap and occasionally kill certain microbes. Furthermore, NETs have been shown to contribute to several noninfectious disease conditions when released by activated neutrophils during inflammation. The identification of NETs has mainly been succeeded by various microscopy techniques, for example, immunofluorescence microscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). Since the last years the development and improvement of new immunofluorescence-based techniques enabled optimized visualization and quantification of NETs. On the one handin vitrolive-cell imaging led to profound new ideas about the mechanisms involved in the formation and functionality of NETs. On the other hand different intravital,in vivo, andin situmicroscopy techniques led to deeper insights into the role of NET formation during health and disease. This paper presents an overview of the main used microscopy techniques to visualize NETs and describes their advantages as well as disadvantages.

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Platelets in atherosclerosis

Thrombosis and Haemostasis ◽

10.1160/th11-08-0592 ◽

2011 ◽

Vol 106 (11) ◽

pp. 827-838 ◽

Cited By ~ 116

Author(s):

Philipp von Hundelshausen ◽

Dirk Lievens

Keyword(s):

Inflammatory Cells ◽

Neutrophil Extracellular Traps ◽

Cellular Interactions ◽

Immune Functions ◽

Leukocyte Activation ◽

Extracellular Traps ◽

Inflammatory Proteins ◽

Inflammatory Milieu ◽

Key Pathways ◽

Do So

SummaryBeyond obvious functions in haemostasis and thrombosis, platelets are considered to be essential in proinflammatory surroundings such as atherosclerosis, allergy, rheumatoid arthritis and even cancer. In atherosclerosis, platelets facilitate the recruitment of inflammatory cells towards the lesion sites and release a plethora of inflammatory mediators, thereby enriching and boosting the inflammatory milieu. Platelets do so by interacting with endothelial cells, circulating leukocytes (monocytes, neutrophils, dendritic cells, T-cells) and progenitor cells. This cross-talk enforces leukocyte activation, adhesion and transmigration. Furthermore, platelets are known to function in innate host defense through the release of antimicrobial peptides and the expression of pattern recognition receptors. In severe sepsis, platelets are able to trigger the formation of neutrophil extracellular traps (NETs), which bind and clear pathogens. The present antiplatelet therapies that target key pathways of platelet activation and aggregation therefore hold the potential to modulate platelet-derived immune functions by reducing cellular interactions of platelets with other immune components and by reducing the secretion of inflammatory proteins into the milieu. The objective of this review is to update and discuss the current perceptions of the platelet immune constituents and their prospect as therapeutic targets in an atherosclerotic setting.

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Angiopoietin 1 release from human neutrophils is independent from neutrophil extracellular traps (NETs)

BMC Immunology ◽

10.1186/s12865-021-00442-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Elcha Charles ◽

Benjamin L. Dumont ◽

Steven Bonneau ◽

Paul-Eduard Neagoe ◽

Louis Villeneuve ◽

...

Keyword(s):

Nuclear Dna ◽

Neutrophil Extracellular Traps ◽

Innate Immune ◽

Human Neutrophils ◽

Extracellular Traps ◽

Pathological Conditions ◽

Healthy Control ◽

Angiopoietin 1

Abstract Background Neutrophils induce the synthesis and release of angiopoietin 1 (Ang1), a cytosolic growth factor involved in angiogenesis and capable of inducing several pro-inflammatory activities in neutrophils. Neutrophils also synthesize and release neutrophil extracellular traps (NETs), comprised from decondensed nuclear DNA filaments carrying proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), proteinase 3 (PR3) and calprotectin (S100A8/S100A9), which together, contribute to the innate immune response against pathogens (e.g., bacteria). NETs are involved in various pathological conditions through pro-inflammatory, pro-thrombotic and endothelial dysfunction effects and have recently been found in heart failure (HF) and type 2 diabetes (T2DM) patients. The aim of the present study was to investigate the role of NETs on the synthesis and release of Ang1 by the neutrophils in patients with T2DM and HF with preserved ejection fraction (HFpEF) (stable or acute decompensated; ADHFpEF) with or without T2DM. Results Our data show that at basal level (PBS) and upon treatment with LPS, levels of NETs are slightly increased in patients suffering from T2DM, HFpEF ± T2DM and ADHF without (w/o) T2DM, whereas this increase was significant in ADHFpEF + T2DM patients compared to healthy control (HC) volunteers and ADHFpEF w/o T2DM. We also observed that treatments with PMA or A23187 increase the synthesis of Ang1 (from 150 to 250%) in HC and this effect is amplified in T2DM and in all cohorts of HF patients. Ang1 is completely released (100%) by neutrophils of all groups and does not bind to NETs as opposed to calprotectin. Conclusions Our study suggests that severely ill patients with HFpEF and diabetes synthesize and release a greater abundance of NETs while Ang1 exocytosis is independent of NETs synthesis.

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Characteristics and Role of Neutrophil Extracellular Traps in Asthma

Inflammation ◽

10.1007/s10753-021-01526-8 ◽

2021 ◽

Author(s):

Fei Chen ◽

Min Yu ◽

Yonghong Zhong ◽

Lina Wang ◽

Huaqiong Huang

Keyword(s):

Systematic Review ◽

Protective Effect ◽

Allergic Asthma ◽

Respiratory Disease ◽

Bronchial Asthma ◽

Inflammatory Cells ◽

Neutrophil Extracellular Traps ◽

Chronic Respiratory Disease ◽

Extracellular Traps

Abstract Asthma is a common chronic respiratory disease that affects millions of people worldwide. The incidence of asthma has continued to increase every year. Bronchial asthma involves a variety of cells, including airway inflammatory cells, structural cells, and neutrophils, which have gained more attention because they secrete substances that play an important role in the occurrence and development of asthma. Neutrophil extracellular traps (NETs) are mesh-like structures composed of DNA, histones, and non-histone molecules that can be secreted from neutrophils. NETs can enrich anti-bacterial substances and limit pathogen migration, thus having a protective effect in case of inflammation. However, despite of their anti-inflammatory properties, NETs have been shown to trigger allergic asthma and worsen asthma progression. Here, we provide a systematic review of the roles of NETs in asthma.

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Neutrophil Extracellular Traps (NETs) in Severe SARS-CoV-2 Lung Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22168854 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8854

Author(s):

Monika Szturmowicz ◽

Urszula Demkow

Keyword(s):

Lung Injury ◽

Nuclear Dna ◽

Viral Infections ◽

Prognostic Significance ◽

Neutrophil Extracellular Traps ◽

Organ Damage ◽

Therapeutic Interventions ◽

Extracellular Traps ◽

Alveolar Capillary

Neutrophil extracellular traps (NETs), built from mitochondrial or nuclear DNA, proteinases, and histones, entrap and eliminate pathogens in the course of bacterial or viral infections. Neutrophils’ activation and the formation of NETs have been described as major risk factors for acute lung injury, multi-organ damage, and mortality in COVID-19 disease. NETs-related lung injury involves both epithelial and endothelial cells, as well as the alveolar-capillary barrier. The markers for NETs formation, such as circulating DNA, neutrophil elastase (NE) activity, or myeloperoxidase-DNA complexes, were found in lung specimens of COVID-19 victims, as well as in sera and tracheal aspirates obtained from COVID-19 patients. DNA threads form large conglomerates causing local obstruction of the small bronchi and together with NE are responsible for overproduction of mucin by epithelial cells. Various components of NETs are involved in the pathogenesis of cytokine storm in SARS-CoV-2 pulmonary disease. NETs are responsible for the interplay between inflammation and thrombosis in the affected lungs. The immunothrombosis, stimulated by NETs, has a poor prognostic significance. Better understanding of the role of NETs in the course of COVID-19 can help to develop novel approaches to the therapeutic interventions in this condition.

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Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation

Thrombosis and Haemostasis ◽

10.1055/s-0039-1678664 ◽

2019 ◽

Vol 119 (04) ◽

pp. 542-552 ◽

Cited By ~ 14

Author(s):

Kristof Van Avondt ◽

Lars Maegdefessel ◽

Oliver Soehnlein

Keyword(s):

Disease Risk ◽

Neutrophil Extracellular Traps ◽

Dnase I ◽

Inflammasome Activation ◽

Extracellular Traps ◽

Thrombotic Complications ◽

Atherothrombotic Disease ◽

Coronary Events ◽

Reactive Oxidants ◽

Net Release

AbstractNeutrophils and neutrophil extracellular traps (NETs) have a robust relationship with atherothrombotic disease risk, which led to the idea that interfering with the release of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute coronary events and the pro-thrombotic state cause markedly elevated levels of circulating deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency and showed a significant benefit for atherothrombotic disease in experimental mouse models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms underlying NET release and atherogenic inflammation have come from transgenic mouse studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic disease has been shown and linked to profound pro-inflammatory and pro-thrombotic effects, complement activation and endothelial dysfunction. Recent studies have shown that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects against atherosclerosis burden, propagation of its thrombotic complications and notably macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol accumulation have emerged as important factors driving NET release, likely involving mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for cardiovascular diseases.

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Neutrophil Extracellular Traps in Arterial and Venous Thrombosis

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0038-1677040 ◽

2019 ◽

Vol 45 (01) ◽

pp. 086-093 ◽

Cited By ~ 41

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.

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