NET Formation in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (10 November 2021) | Viewed by 24046

Special Issue Editors


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Guest Editor
Medizinische Klinik 3, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
Interests: neutrophil and NET-driven induction or resolution of inflammation; NET-related occlusive diseases; NET formation and aggregation

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Guest Editor
Department of Pediatric Surgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
Interests: neutrophils; neutrophil extracellular traps; pediatric diseases
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Guest Editor
Medizinische Klinik 3, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
Interests: neutrophil biology and neuro-immune-regulation
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Guest Editor
1. Department of Pediatric Surgery, University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
2. Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany
3. Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Ulmenweg 18, 91054 Erlangen, Germany
Interests: NET formation; NET maturation; inflammation; immunothrombosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neutrophils and the formation of neutrophil extracellular traps (NETs) are both evolutionarily conserved. Naturally-occurring deficiencies of both are scarce. In humans, even temporary lack of neutrophils and, consequently, NET formation is fatal. This strongly suggests that they serve crucial functions in host defense. This is supported by the observation that many bacteria bear DNases as virulence factors. Various forms of this enzyme are secreted from pus-forming bacteria and from those associated with advanced periodontal disease. However, there are also pathogenicities caused by overwhelming NET formation, reduced clearance of NETs or spreading inflammatory NET degradation products. In high densities, such as those found in inflamed tissues or in conditions of systemic leukocytosis, NETs tend to become matted and form large aggregates. Extensive generation of the latter bears the risk of occluding tubular structures of the body such as vessel or secretory ducts (e.g., pancreatic or biliary ducts). Dependent on the conditions, the clogging affects veins or arteries, big, intermediate or small vessels, as well as the capillary bed. These occlusions and result in thromboembolic events or closure of the microvasculature.

This Special Issue aims to summarize the current knowledge on NET formation in relation to its clinical impact. Reports on disease ameliorating as well as exacerbating conditions are welcome. We ask authors to focus on emerging promising targets that link in vitro data, animal experiments, and translational research with clinical studies. We also encourage authors to present non-canonical views in opinion papers.

We look forward to receiving your contributions.

Dr. Aparna Mahajan
Dr. Jasmin Knopf
Dr. Luis E. Munoz
Prof. Martin Herrmann
Guest Editors

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Keywords

  • NET formation and aggregation
  • Tissue damage by NETs and NET degradation products
  • Vascular and ductal occlusion
  • NETs in wound healing
  • NET-driven inflammation versus resolution of inflammation

Published Papers (7 papers)

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Editorial

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2 pages, 178 KiB  
Editorial
Formation and Clearance of NETs in Health and Disease
by Jasmin Knopf, Aparna Mahajan, Luis E. Muñoz and Martin Herrmann
Cells 2022, 11(24), 4022; https://doi.org/10.3390/cells11244022 - 12 Dec 2022
Cited by 3 | Viewed by 1172
Abstract
Neutrophils are the most abundant innate immune cells in humans and the first line of defense against invading pathogens [...] Full article
(This article belongs to the Special Issue NET Formation in Health and Disease)

Research

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12 pages, 2619 KiB  
Article
NET Formation in Systemic Lupus Erythematosus: Changes during the COVID-19 Pandemic
by Jasmin Knopf, Johanna Sjöwall, Martina Frodlund, Jorma Hinkula, Martin Herrmann and Christopher Sjöwall
Cells 2022, 11(17), 2619; https://doi.org/10.3390/cells11172619 - 23 Aug 2022
Cited by 4 | Viewed by 2500
Abstract
The severity of the coronavirus disease in 2019 (COVID-19) is strongly linked to a dysregulated immune response. This fuels the fear of severe disease in patients with autoimmune disorders continuously using immunosuppressive/immunomodulating medications. One complication of COVID-19 is thromboembolism caused by intravascular aggregates [...] Read more.
The severity of the coronavirus disease in 2019 (COVID-19) is strongly linked to a dysregulated immune response. This fuels the fear of severe disease in patients with autoimmune disorders continuously using immunosuppressive/immunomodulating medications. One complication of COVID-19 is thromboembolism caused by intravascular aggregates of neutrophil extracellular traps (NETs) occluding the affected vessels. Like COVID-19, systemic lupus erythematosus (SLE) is characterized by, amongst others, an increased risk of thromboembolism. An imbalance between NET formation and clearance is suggested to play a prominent role in exacerbating autoimmunity and disease severity. Serologic evidence of exposure to SARS-CoV-2 has a minor impact on the SLE course in a Swedish cohort reportedly. Herein, we assessed NET formation in patients from this cohort by neutrophil elastase (NE) activity and the presence of cell-free DNA, MPO-DNA, and NE-DNA complexes and correlated the findings to the clinical parameters. The presence of NE-DNA complexes and NE activity differed significantly in pre-pandemic versus pandemic serum samples. The latter correlated significantly with the hemoglobin concentration, blood cell counts, and complement protein 3 and 4 levels in the pre-pandemic but only with the leukocyte count and neutrophil levels in the pandemic serum samples. Taken together, our data suggest a change, especially in the NE activity independent of exposure to SARS-CoV-2. Full article
(This article belongs to the Special Issue NET Formation in Health and Disease)
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9 pages, 1002 KiB  
Communication
IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients
by Léonie A. N. Staats, Hella Pfeiffer, Jasmin Knopf, Aylin Lindemann, Julia Fürst, Andreas E. Kremer, Holger Hackstein, Markus F. Neurath, Luis E. Muñoz, Susanne Achenbach, Moritz Leppkes, Martin Herrmann, Georg Schett and Ulrike Steffen
Cells 2020, 9(12), 2676; https://doi.org/10.3390/cells9122676 - 12 Dec 2020
Cited by 24 | Viewed by 4376
Abstract
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune [...] Read more.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome. Full article
(This article belongs to the Special Issue NET Formation in Health and Disease)
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18 pages, 13970 KiB  
Article
Drug Crystal-Related Gastrointestinal Complications Involve Crystal-Induced Release of Neutrophil and Monocyte Extracellular Traps
by Tehyung Kim, Sueli de Oliveira Silva Lautenschlager, Qiuyue Ma, Kathrin Eller, Marion Julia Pollheimer, Danielle Lazarin-Bidóia, Celso Vataru Nakamura, Hans-Joachim Anders and Stefanie Steiger
Cells 2020, 9(11), 2481; https://doi.org/10.3390/cells9112481 - 15 Nov 2020
Cited by 14 | Viewed by 2913
Abstract
Ion-exchange resins are commonly used to manage complications of chronic kidney disease, such as hyperphosphatemia, hyperkalemia, and hypercholesterolemia. Occasionally, these drugs can irritate the gastrointestinal lining and cause life-threatening intestinal necrosis. Currently, the pathophysiology of drug crystal-induced intestinal necrosis is not well understood. [...] Read more.
Ion-exchange resins are commonly used to manage complications of chronic kidney disease, such as hyperphosphatemia, hyperkalemia, and hypercholesterolemia. Occasionally, these drugs can irritate the gastrointestinal lining and cause life-threatening intestinal necrosis. Currently, the pathophysiology of drug crystal-induced intestinal necrosis is not well understood. We hypothesized that crystals of ion-exchange resins like sevelamer, polystyrene sulfonate, and cholestyramine can trigger the formation of neutrophil and monocyte extracellular traps by contributing to intestinal barrier dysfunction. Light and fluorescence microscopy of the colonic resection specimen from a patient with chronic kidney disease revealed severe intestinal necrosis, ulceration, sevelamer crystals, and inflammation upon oral intake of sevelamer, as well as the formation of neutrophil extracellular traps in proximity to small sevelamer crystals. Indeed, drug crystals reduced metabolic activity and induced barrier dysfunction and cell death in human intestinal epithelial cells in vitro. In addition, drug crystals triggered the release of neutrophil and monocyte extracellular traps. Taken together, these data raise the possibility that besides other factors including chronic kidney disease, diabetes mellitus, and hypertension, drug crystals may further amplify a pre-existing barrier dysfunction and necroinflammation in a crescendo of local intestinal necrosis and systemic inflammation/infection, as occasionally observed in patients on ion-exchange resin therapy. Full article
(This article belongs to the Special Issue NET Formation in Health and Disease)
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14 pages, 2290 KiB  
Article
Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones
by Mirco Schapher, Michael Koch, Daniela Weidner, Michael Scholz, Stefan Wirtz, Aparna Mahajan, Irmgard Herrmann, Jeeshan Singh, Jasmin Knopf, Moritz Leppkes, Christine Schauer, Anika Grüneboom, Christoph Alexiou, Georg Schett, Heinrich Iro, Luis E. Muñoz and Martin Herrmann
Cells 2020, 9(9), 2139; https://doi.org/10.3390/cells9092139 - 22 Sep 2020
Cited by 25 | Viewed by 3554
Abstract
Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial [...] Read more.
Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth. Full article
(This article belongs to the Special Issue NET Formation in Health and Disease)
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Review

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16 pages, 1046 KiB  
Review
NETs Are Double-Edged Swords with the Potential to Aggravate or Resolve Periodontal Inflammation
by Ljubomir Vitkov, Bernd Minnich, Jasmin Knopf, Christine Schauer, Matthias Hannig and Martin Herrmann
Cells 2020, 9(12), 2614; https://doi.org/10.3390/cells9122614 - 5 Dec 2020
Cited by 20 | Viewed by 3693
Abstract
Periodontitis is a general term for diseases characterised by inflammatory destruction of tooth-supporting tissues, gradual destruction of the marginal periodontal ligament and resorption of alveolar bone. Early-onset periodontitis is due to disturbed neutrophil extracellular trap (NET) formation and clearance. Indeed, mutations that inactivate [...] Read more.
Periodontitis is a general term for diseases characterised by inflammatory destruction of tooth-supporting tissues, gradual destruction of the marginal periodontal ligament and resorption of alveolar bone. Early-onset periodontitis is due to disturbed neutrophil extracellular trap (NET) formation and clearance. Indeed, mutations that inactivate the cysteine proteases cathepsin C result in the massive periodontal damage seen in patients with deficient NET formation. In contrast, exaggerated NET formation due to polymorphonuclear neutrophil (PMN) hyper-responsiveness drives the pathology of late-onset periodontitis by damaging and ulcerating the gingival epithelium and retarding epithelial healing. Despite the gingival regeneration, periodontitis progression ends with almost complete loss of the periodontal ligament and subsequent tooth loss. Thus, NETs help to maintain periodontal health, and their dysregulation, either insufficiency or surplus, causes heavy periodontal pathology and edentulism. Full article
(This article belongs to the Special Issue NET Formation in Health and Disease)
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25 pages, 3894 KiB  
Review
On Neutrophil Extracellular Trap (NET) Removal: What We Know Thus Far and Why So Little
by Michal Santocki and Elzbieta Kolaczkowska
Cells 2020, 9(9), 2079; https://doi.org/10.3390/cells9092079 - 11 Sep 2020
Cited by 29 | Viewed by 5086
Abstract
Although neutrophil extracellular traps (NETs) were discovered only 16 years ago, they have already taken us from heaven to hell as we learned that apart from beneficial trapping of pathogens, they cause, or contribute to, numerous disorders. The latter is connected to their [...] Read more.
Although neutrophil extracellular traps (NETs) were discovered only 16 years ago, they have already taken us from heaven to hell as we learned that apart from beneficial trapping of pathogens, they cause, or contribute to, numerous disorders. The latter is connected to their persistent presence in the blood or tissue, and we hardly know how they are removed in mild pathophysiological conditions and why their removal is impaired in multiple severe pathological conditions. Herein, we bring together all data available up till now on how NETs are cleared—from engaged cells, their phenotypes, to involved enzymes and molecules. Moreover, we hypothesize on why NET removal is challenged in multiple disorders and propose further directions for studies on NET removal as well as possible therapeutic strategies to have them cleared. Full article
(This article belongs to the Special Issue NET Formation in Health and Disease)
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