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Neutrophil Extracellular Traps (NETs) in Immunity and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 23202

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Special Issue Editor

Dr. Małgorzata Wachowska

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Guest Editor

Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland
Interests: neutrophils; neutrophil asociated autophagy; neutrophils extracelular traps; neutrophils in immune reponse; neutrophils PI3K signalling; neutrophils role in development and progression of cancer diseases; tumor asociated neutrophils

Special Issue Information

Dear Colleagues,

Currently, extensive part of research focus mainly on adaptive immune response and its broad application. However, human death rates is highly influenced by such diseases as sepsis, multi resistant microbes, autoimmune disorders and cancer, where innate immunity plays a leading role. Therefore, our attention should be paid to innate immune response, especially, from my point of view, to neutrophils playing an invaluable role in host immune defence. These cells are directed by cytokines and other stimuli into infected tissues, where they eliminate invading microbes. Notably, successful defence by neutrophils is often associated with inflammatory tissue damage and several diseases including allergy, autoimmune diseases, atherosclerosis, thrombus formation and metabolic disorders. It has been linked to capability of activated neutrophils to release decondensed chromatin decorated with granular proteins known as neutrophil extracellular traps (NETs). NETs act as a scaffold for the aggregation of viable, necrotic and apoptotic cells as well as crystals and microbes. Importantly, under specific conditions NETs will act as inflammatory or anti-inflammatory process. Although a lot of effort was put to the studies concerning NETs release, we still need to broaden our knowledge of this unique feature. In term of currently available data showing contribution of NETs to various pathological conditions and cancer metastasis, deeper understanding of the mechanisms of NETs release as well as it’s role in immue response and diseases, is of great importance.

This special issue is focused on update of current research on NETs in immunity and disease that can bring us closer to understand this phenomenon and enable development of new therapeutic strategies concerning various pathological conditions related to excessive NETs release. Both review and original article, covering basic, translational or clinical supported with molecular data research, are welcomed.

Dr. Małgorzata Wachowska
Guest Editor

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Keywords

neutrophils
neutrophils functions
neutrophil extracelular traps (NETs)
NETs biology
NETs in autoimmune diseases
NETs in immune reponse
NETs in development and progression of cancer diseases

Published Papers (9 papers)

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Research

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14 pages, 2761 KiB

Open AccessArticle

Visualization of Nuclease- and Serum-Mediated Chromatin Degradation with DNA–Histone Mesostructures

by Midori L. Wasielewski, Katherine Nguyen, Srilakshmi Yalavarthi, Pallavi Ekbote, Priyan D. Weerappuli, Jason S. Knight and Shuichi Takayama

Int. J. Mol. Sci. 2023, 24(4), 3222; https://doi.org/10.3390/ijms24043222 - 6 Feb 2023

Viewed by 1572

Abstract

This study analyzed the nuclease- and serum-driven degradation of millimeter-scale, circular DNA–histone mesostructures (DHMs). DHMs are bioengineered chromatin meshes of defined DNA and histone compositions designed as minimal mimetics of physiological extracellular chromatin structures, such as neutrophil extracellular traps (NETs). Taking advantage of the defined circular shape of the DHMs, an automated time-lapse imaging and image analysis method was developed and used to track DHM degradation and shape changes over time. DHMs were degraded well by 10 U/mL concentrations of deoxyribonuclease I (DNase I) but not by the same level of micrococcal nuclease (MNase), whereas NETs were degraded well by both nucleases. These comparative observations suggest that DHMs have a less accessible chromatin structure compared to NETs. DHMs were degraded by normal human serum, although at a slower rate than NETs. Interestingly, time-lapse images of DHMs revealed qualitative differences in the serum-mediated degradation process compared to that mediated by DNase I. Importantly, despite their reduced susceptibility to degradation and compositional simplicity, the DHMs mimicked NETs in being degraded to a greater extent by normal donor serum compared to serum from a lupus patient with high disease activity. These methods and insights are envisioned to guide the future development and expanded use of DHMs, beyond the previously reported antibacterial and immunostimulatory analyses, to extracellular chromatin-related pathophysiological and diagnostic studies. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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14 pages, 2272 KiB

Open AccessArticle

Febrile-Range Hyperthermia Can Prevent Toxic Effects of Neutrophil Extracellular Traps on Mesenchymal Stem Cells

by Caren Linnemann, Andreas K. Nussler, Tina Histing and Sabrina Ehnert

Int. J. Mol. Sci. 2022, 23(24), 16208; https://doi.org/10.3390/ijms232416208 - 19 Dec 2022

Cited by 2 | Viewed by 1479

Abstract

Fracture healing is characterized by an inflammatory phase directly after fracture which has a strong impact on the healing outcome. Neutrophils are strong contributors here and can release neutrophil extracellular traps (NETs). NETs are found after trauma, originally thought to capture pathogens. However, they can lead to tissue damage and impede wound healing processes. Their role in fracture healing remains unclear. In this study, the effect of isolated NETs on the function of bone-forming mesenchymal stem cells (SCP-1 cells) was examined. NETs were isolated from stimulated healthy neutrophils and viability, migration, and differentiation of SCP-1 cells were analyzed after the addition of NETs. NETs severely impaired the viability of SCP-1 cells, induced necrosis and already nontoxic concentrations reduced migration significantly. Short-term incubation with NETs had a persistent negative effect on osteogenic differentiation, as measured by AP activity and matrix formation. The addition of DNase or protease inhibitors failed to reverse the negative effect of NETs, whereas a short febrile-range temperature treatment successfully reduced the toxicity and membrane destruction. Thus, the possible modification of the negative effects of NETs in fracture hematomas could be an interesting new target to improve bone healing, particularly in patients with chronic diseases such as diabetes. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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20 pages, 12778 KiB

Open AccessArticle

A Pleomorphic Puzzle: Heterogeneous Pulmonary Vascular Occlusions in Patients with COVID-19

by Jeeshan Singh, Irmgard Herrmann, Aparna Mahajan, Christine Schauer, Xiaomei Shan, Arndt Hartmann, Ralf J. Rieker, Katja Evert, Christina Falkeis, Elisabeth Naschberger, Saskia von Stillfried, Peter Boor, Luis E. Muñoz, Georg Schett, Martin Herrmann and Jasmin Knopf

Int. J. Mol. Sci. 2022, 23(23), 15126; https://doi.org/10.3390/ijms232315126 - 1 Dec 2022

Cited by 1 | Viewed by 1465

Abstract

Vascular occlusions in patients with coronavirus diseases 2019 (COVID-19) have been frequently reported in severe outcomes mainly due to a dysregulation of neutrophils mediating neutrophil extracellular trap (NET) formation. Lung specimens from patients with COVID-19 have previously shown a dynamic morphology, categorized into three types of pleomorphic occurrence based on histological findings in this study. These vascular occlusions in lung specimens were also detected using native endogenous fluorescence or NEF in a label-free method. The three types of vascular occlusions exhibit morphology of DNA rich neutrophil elastase (NE) poor (type I), NE rich DNA poor (type II), and DNA and NE rich (type III) cohort of eleven patients with six males and five females. Age and gender have been presented in this study as influencing variables linking the occurrence of several occlusions with pleomorphic contents within a patient specimen and amongst them. This study reports the categorization of pleomorphic occlusions in patients with COVID-19 and the detection of these occlusions in a label-free method utilizing NEF. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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22 pages, 5218 KiB

Open AccessArticle

New Insights into Neutrophil Extracellular Trap (NETs) Formation from Porcine Neutrophils in Response to Bacterial Infections

by Marta C. Bonilla, Oriana N. Quiros, Michael Wendt, Isabel Hennig-Pauka, Matthias Mörgelin, Maren von Köckritz-Blickwede and Nicole de Buhr

Int. J. Mol. Sci. 2022, 23(16), 8953; https://doi.org/10.3390/ijms23168953 - 11 Aug 2022

Cited by 8 | Viewed by 2427

Abstract

Actinobacillus pleuropneumoniae (A.pp, Gram negative) and Streptococcus (S.) suis (Gram positive) can cause severe diseases in pigs. During infection, neutrophils infiltrate to counteract these pathogens with phagocytosis and/or neutrophil extracellular traps (NETs). NETs consist of a DNA-backbone spiked with antimicrobial components. The NET formation mechanisms in porcine neutrophils as a response to both of the pathogens are not entirely clear. The aim of this study was to investigate whether A.pp (serotype 2, C3656/0271/11) and S. suis (serotype 2, strain 10) induce NETs by NADPH oxidase- or CD18-dependent mechanisms and to characterize phenotypes of NETs in porcine neutrophils. Therefore, we investigated NET induction in porcine neutrophils in the presence and absence of NET inhibitors and quantified NETs after 3 h. Furthermore, NETosis and phagocytosis were investigated by transmission electron microscopy after 30 min to characterize different phenotypes. A.pp and S. suis induce NETs that are mainly ROS-dependent. A.pp induces NETs that are partially CD18-dependent. Thirty minutes after infection, both of the pathogens induced a vesicular NET formation with only slight differences. Interestingly, some neutrophils showed only NET-marker positive phagolysosomes, but no NET-marker positive vesicles. Other neutrophils showed vesicular NETs and only NET-marker negative phagolysosomes. In conclusion, both of the pathogens induce ROS-dependent NETs. Vesicular NETosis and phagocytosis occur in parallel in porcine neutrophils in response to S. suis serotype 2 and A.pp serotype 2. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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16 pages, 2337 KiB

Open AccessArticle

Lack of Functional P110δ Affects Expression of Activation Marker CD80 but Does Not Influence Functions of Neutrophils

by Aneta Manda-Handzlik, Agnieszka Mroczek, Weronika Kuźmicka, Adrianna Cieloch, Zuzanna Homoncik, Angelika Muchowicz, Urszula Demkow and Małgorzata Wachowska

Int. J. Mol. Sci. 2022, 23(12), 6361; https://doi.org/10.3390/ijms23126361 - 7 Jun 2022

Viewed by 1979

Abstract

Neutrophils are specialized immune cells that are essential constituents of the innate immune response. They defend the organism against pathogens through various mechanisms. It was reported that phosphatidylinositols are key players in neutrophil functions, especially in the activity of class-I phosphoinositide 3-kinases (PI3Ks). P110δ, one of the PI3K subunits, is mostly expressed in immune cells, and its activity plays an important role in inflammatory responses. The aim of this study was to investigate the role of p110δ in neutrophil antimicrobial functions, activation status and cytokine production. To this end, we used bone marrow and splenic neutrophils isolated from a murine model expressing catalytically inactive p110δ^D910A/D910A. The level of phagocytosis and degranulation, the expressions of activation markers and cytokine production were determined by flow cytometry. ROS generation and NET release were assessed by fluorometry and fluorescent microscopy. We observed a significantly higher percentage of CD80-positive cells among the splenic granulocytes and found granulocytes subpopulations of differing phenotypes between WT and p110δ^D910A/D910A mice by multiparametric tSNE analysis. Moreover, we detected some differences in the expressions of activation markers, intracellular production of cytokines and bacterial killing. However, we did not observe any alterations in the selected neutrophil functions in p110δ mutant mice. Altogether, our data suggest that the catalytic p110 subunit(s), other than p110δ, is a key player in most neutrophil functions in mice. A follow-up study to correlate these in vitro results with in vivo observations is highly recommended. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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Review

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24 pages, 1432 KiB

Open AccessReview

Putative Role of Neutrophil Extracellular Trap Formation in Chronic Myeloproliferative Neoplasms

by Dragana C. Marković, Irina S. Maslovarić, Marijana Kovačić, Sanja Vignjević Petrinović and Vesna Lj. Ilić

Int. J. Mol. Sci. 2023, 24(5), 4497; https://doi.org/10.3390/ijms24054497 - 24 Feb 2023

Cited by 4 | Viewed by 2422

Abstract

Myeloproliferative neoplasms (MPNs) are hematologic malignancies characterized by gene mutations that promote myeloproliferation and resistance to apoptosis via constitutively active signaling pathways, with Janus kinase 2-signal transducers and the activators of transcription (JAK-STAT) axis as a core part. Chronic inflammation has been described as a pivot for the development and advancement of MPNs from early stage cancer to pronounced bone marrow fibrosis, but there are still unresolved questions regarding this issue. The MPN neutrophils are characterized by upregulation of JAK target genes, they are in a state of activation and with deregulated apoptotic machinery. Deregulated neutrophil apoptotic cell death supports inflammation and steers them towards secondary necrosis or neutrophil extracellular trap (NET) formation, a trigger of inflammation both ways. NETs in proinflammatory bone marrow microenvironment induce hematopoietic precursor proliferation, which has an impact on hematopoietic disorders. In MPNs, neutrophils are primed for NET formation, and even though it seems obvious for NETs to intervene in the disease progression by supporting inflammation, no reliable data are available. We discuss in this review the potential pathophysiological relevance of NET formation in MPNs, with the intention of contributing to a better understanding of how neutrophils and neutrophil clonality can orchestrate the evolution of a pathological microenvironment in MPNs. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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Graphical abstract

15 pages, 1141 KiB

Open AccessReview

Neutrophils in Dendritic Cell-Based Cancer Vaccination: The Potential Roles of Neutrophil Extracellular Trap Formation

by Lily Chan, Geoffrey A. Wood, Sarah K. Wootton, Byram W. Bridle and Khalil Karimi

Int. J. Mol. Sci. 2023, 24(2), 896; https://doi.org/10.3390/ijms24020896 - 4 Jan 2023

Cited by 3 | Viewed by 3274

Abstract

Neutrophils have conflicting roles in the context of cancers, where they have been associated with contributing to both anti-tumor and pro-tumor responses. Their functional heterogenicity is plastic and can be manipulated by environmental stimuli, which has fueled an area of research investigating therapeutic strategies targeting neutrophils. Dendritic cell (DC)-based cancer vaccination is an immunotherapy that has exhibited clinical promise but has shown limited clinical efficacy. Enhancing our understanding of the communications occurring during DC cancer vaccination can uncover opportunities for enhancing the DC vaccine platform. There have been observed communications between neutrophils and DCs during natural immune responses. However, their crosstalk has been poorly studied in the context of DC vaccination. Here, we review the dual functionality of neutrophils in the context of cancers, describe the crosstalk between neutrophils and DCs during immune responses, and discuss their implications in DC cancer vaccination. This discussion will focus on how neutrophil extracellular traps can influence immune responses in the tumor microenvironment and what roles they may play in promoting or hindering DC vaccine-induced anti-tumor efficacy. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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18 pages, 774 KiB

Open AccessReview

Eating the Enemy: Mycoplasma Strategies to Evade Neutrophil Extracellular Traps (NETs) Promoting Bacterial Nucleotides Uptake and Inflammatory Damage

by Carla Cacciotto and Alberto Alberti

Int. J. Mol. Sci. 2022, 23(23), 15030; https://doi.org/10.3390/ijms232315030 - 30 Nov 2022

Cited by 4 | Viewed by 4184

Abstract

Neutrophils are effector cells involved in the innate immune response against infection; they kill infectious agents in the intracellular compartment (phagocytosis) or in the extracellular milieu (degranulation). Moreover, neutrophils release neutrophil extracellular traps (NETs), complex structures composed of a scaffold of decondensed DNA associated with histones and antimicrobial compounds; NETs entrap infectious agents, preventing their spread and promoting their clearance. NET formation is triggered by microbial compounds, but many microorganisms have evolved several strategies for NET evasion. In addition, the dysregulated production of NETs is associated with chronic inflammatory diseases. Mycoplasmas are reduced genome bacteria, able to induce chronic infections with recurrent inflammatory symptoms. Mycoplasmas’ parasitic lifestyle relies on metabolite uptake from the host. Mycoplasmas induce NET release, but their surface or secreted nucleases digest the NETs’ DNA scaffold, allowing them to escape from entrapment and providing essential nucleotide precursors, thus promoting the infection. The presence of Mycoplasma species has been associated with chronic inflammatory disorders, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, and cancer. The persistence of mycoplasma infection and prolonged NET release may contribute to the onset of chronic inflammatory diseases and needs further investigation and insights. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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14 pages, 1000 KiB

Open AccessReview

Neutrophils’ Extracellular Trap Mechanisms: From Physiology to Pathology

by Janina Schoen, Maximilien Euler, Christine Schauer, Georg Schett, Martin Herrmann, Jasmin Knopf and Kursat Oguz Yaykasli

Int. J. Mol. Sci. 2022, 23(21), 12855; https://doi.org/10.3390/ijms232112855 - 25 Oct 2022

Cited by 16 | Viewed by 3187

Abstract

Neutrophils are an essential part of the innate immune system and the first line of defense against invading pathogens. They phagocytose, release granular contents, produce reactive oxygen species, and form neutrophil extracellular traps (NETs) to fight pathogens. With the characterization of NETs and their components, neutrophils were identified as players of the innate adaptive crosstalk. This has placed NETs at the center not only of physiological but also pathological processes. Aside from their role in pathogen uptake and clearance, NETs have been demonstrated to contribute to the resolution of inflammation by forming aggregated NETs able to degrade inflammatory mediators. On the other hand, NETs have the potential to foster severe pathological conditions. When homeostasis is disrupted, they occlude vessels and ducts, serve as sources of autoantigens and danger or damage associated molecular patterns, directly damage tissues, and exaggerate complement activity and inflammation. This review focusses on the understanding of NETs from their formation to their functions in both physiological and pathological processes. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases)

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