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Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition

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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 (20 November 2024) | Viewed by 9951

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Dr. Jasmin Knopf

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Department of Pediatric Surgery, University Medical Center Mannheim, University Heidelberg, 68167 Mannheim, Germany
Interests: neutrophils; neutrophil extracellular traps; pediatric diseases, pediatric cancers
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Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue on “Neutrophil Extracellular Traps (NETs) in Immunity and Diseases” (https://www.mdpi.com/journal/ijms/special_issues/NETs_immune).

Currently, research in this area has mainly focused on adaptive immune response and its broad application. However, human death rates are highly influenced by diseases such as sepsis, multiresistant microbes, autoimmune disorders and cancer, in which innate immunity plays a leading role. Therefore, greater attention should be paid to the innate immune response, and especially to neutrophils, which play an invaluable role in host immune defence. Cytokines and other stimuli direct these cells into infected tissues, where they eliminate invading microbes. Notably, successful neutrophil defence is often associated with inflammatory tissue damage and diseases including allergy, autoimmune diseases, atherosclerosis, thrombus formation, and metabolic disorders. This has been linked to the 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 act as an inflammatory or anti-inflammatory process.

Although significant efforts have been made to study NETs’ release, we still need to broaden our knowledge of this unique feature. In terms of the currently available data showing the contribution of NETs to various pathological conditions and cancer metastasis, gaining a deeper understanding of the mechanisms of NETs’ release, as well as their role in the immune response and diseases, is of great importance. Additionally, the degradation of NETs and their clearance is only partially understood and warrants further research.

The focus of this Special Issue is to update current research on NETs in immunity and disease, improving our understanding of this phenomenon and enabling the development of new therapeutic strategies concerning various pathological conditions related to excessive NET release and/or incomplete degradation. Both review and original articles covering basic, translational or clinical molecular-data-supported research are welcome.

Dr. Jasmin Knopf
Guest Editor

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Keywords

neutrophils
neutrophil functions
neutrophil extracellular traps (NETs)
NETs biology
NETs in autoimmune diseases
NETs in immune response
NETs in development and progression of cancer diseases
NETs in immunothrombosis, degradation of NETs

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Published Papers (8 papers)

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15 pages, 24149 KiB

Open AccessCommunication

Neutrophil Extracellular Traps in Pediatric Inflammatory Bowel Disease: A Potential Role in Ulcerative Colitis

by Rachel Shukrun, Victoria Fidel, Szilvia Baron, Noga Unger, Yoav Ben-Shahar, Shlomi Cohen, Ronit Elhasid and Anat Yerushalmy-Feler

Int. J. Mol. Sci. 2024, 25(20), 11126; https://doi.org/10.3390/ijms252011126 - 16 Oct 2024

Viewed by 687

Abstract

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gut affecting both adults and children. Neutrophil extracellular traps (NETs) are structures released by activated neutrophils, potentially contributing to tissue damage in various diseases. This study aimed to explore the presence and role of NETs in pediatric IBD. We compared intestinal biopsies and peripheral blood from 20 pediatric IBD patients (UC and CD) to controls. Biopsy staining and techniques for neutrophil activation were used to assess neutrophil infiltration and NET formation. We also measured the enzymatic activity of key NET proteins and evaluated NET formation in UC patients in remission. Both UC and CD biopsies showed significantly higher levels of neutrophils and NETs compared to controls (p < 0.01), with UC exhibiting the strongest association. Peripheral blood neutrophils from UC patients at diagnosis displayed increased NET formation compared to controls and CD patients. Interestingly, NET formation normalized in UC patients following remission-inducing treatment. This pilot study suggests a potential role for NETs in pediatric IBD, particularly UC. These findings warrant further investigation into the mechanisms of NET involvement and the potential for targeting NET formation as a therapeutic strategy. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition)

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13 pages, 1171 KiB

Open AccessArticle

The Impact of Disease Severity on the Serum Levels of Significant Neutrophil Extracellular Trap (NET) Proteins in Patients with Psoriasis

by Joanna Czerwińska and Agnieszka Owczarczyk-Saczonek

Int. J. Mol. Sci. 2024, 25(19), 10671; https://doi.org/10.3390/ijms251910671 - 3 Oct 2024

Viewed by 1416

Abstract

Psoriasis is an inflammatory skin disease with various symptoms of differing severities and with the reported prominent involvement of neutrophil extracellular traps (NETs). The excitation of neutrophils, e.g., by interleukin 8 (IL-8) or lipopolysaccharide (LPS), leads to the citrullination of histones and the release of protein–DNA complexes into the extracellular space, where they are digested by DNases. Our aim was to explore data on the levels of protein-complexed DNAs neutrophil elastase–DNA (NE-DNA) and myeloperoxidase–DNA (MPO-DNA), citrullinated histones (citH2, citH3, citH4), and NET-degrading enzyme DNase I in the serum of psoriatic patients with varying severities of clinical symptoms assessed with the Psoriasis Area Severity Index (PASI), Body Surface Area (BSA), and Dermatology Life Quality Index (DLQI) scores. The levels of factors were detected in 52 patients with psoriasis and 22 healthy volunteers by the enzyme-linked immunosorbent assay (ELISA). The results showed the elevated levels of NE-DNA, MPO-DNA, citH3, and DNase I in the patients with psoriasis compared to healthy volunteers (p < 0.05). Additionally, changes were noticed in the levels of NE-DNA, citH3, and DNase I, depending on the severity of symptoms (p < 0.05). In mild psoriasis (PASI < 10, BSA < 10, DLQI < 10), the suppressing activity of the enzyme caused the impaired ability to remove the physiological level of NETs, whereas in moderate to severe psoriasis (PASI ≥ 10, BSA ≥ 10, DLQI ≥ 10), the enhanced activity of DNase I failed to remove NETs due to the observed overexpression. It may, thus, be concluded that the mechanism of action of NETs, which play an undeniable role in psoriatic diseases, seem to follow two different paths depending on the severity of disease, which may be crucial in selecting potential anti-NET treatment methods. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition)

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18 pages, 21637 KiB

Open AccessArticle

Complement-Mediated Two-Step NETosis: Serum-Induced Complement Activation and Calcium Influx Generate NADPH Oxidase-Dependent NETs in Serum-Free Conditions

by Maria Maqsood, Samuel Suntharalingham, Meraj Khan, Carolina G. Ortiz-Sandoval, Wouter J. C. Feitz, Nades Palaniyar and Christoph Licht

Int. J. Mol. Sci. 2024, 25(17), 9625; https://doi.org/10.3390/ijms25179625 - 5 Sep 2024

Viewed by 861

Abstract

The complement system and neutrophils play crucial roles in innate immunity. Neutrophils release neutrophil extracellular traps (NETs), which are composed of decondensed DNA entangled with granular contents, as part of their innate immune function. Mechanisms governing complement-mediated NET formation remain unclear. In this study, we tested a two-step NETosis mechanism, as follows: classical complement-mediated neutrophil activation in serum and subsequent NET formation in serum-free conditions, using neutrophils from healthy donors, endothelial cells, and various assays (Fluo-4AM, DHR123, and SYTOX), along with flow cytometry and confocal microscopy. Our findings reveal that classical complement activation on neutrophils upregulated the membrane-anchored complement regulators CD46, CD55, and CD59. Additionally, complement activation increased CD11b on neutrophils, signifying activation and promoting their attachment to endothelial cells. Complement activation induced calcium influx and citrullination of histone 3 (CitH3) in neutrophils. However, CitH3 formation alone was insufficient for NET generation. Importantly, NET formation occurred only when neutrophils were in serum-free conditions. In such environments, neutrophils induced NADPH oxidase-dependent reactive oxygen species (ROS) production, leading to NET formation. Hence, we propose that complement-mediated NET formation involves a two-step process, as follows: complement deposition, neutrophil priming, calcium influx, CitH3 formation, and attachment to endothelial cells in serum. This is followed by NADPH-dependent ROS production and NET completion in serum-free conditions. Understanding this process may unveil treatment targets for pathologies involving complement activation and NET formation. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition)

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12 pages, 2904 KiB

Open AccessArticle

Sodium Acetate Enhances Neutrophil Extracellular Trap Formation via Histone Acetylation Pathway in Neutrophil-like HL-60 Cells

by Hiroyuki Yasuda, Yutaka Takishita, Akihiro Morita, Tomonari Tsutsumi, Naoya Nakagawa and Eisuke F. Sato

Int. J. Mol. Sci. 2024, 25(16), 8757; https://doi.org/10.3390/ijms25168757 - 11 Aug 2024

Viewed by 1136

Abstract

Neutrophil extracellular trap formation has been identified as a new cell death mediator, termed NETosis, which is distinct from apoptosis and necrosis. NETs capture foreign substances, such as bacteria, by releasing DNA into the extracellular environment, and have been associated with inflammatory diseases and altered immune responses. Short-chain fatty acids, such as acetate, are produced by the gut microbiota and reportedly enhance innate immune responses; however, the underlying molecular mechanisms remain unclear. Here, we investigated the effects of sodium acetate, which has the highest SCFA concentration in the blood and gastrointestinal tract, on NETosis by focusing on the mechanisms associated with histone acetylation in neutrophil-like HL-60 cells. Sodium acetate enhanced NETosis, as shown by fluorescence staining with SYTOX green, and the effect was directly proportional to the treatment duration (16–24 h). Moreover, the addition of sodium acetate significantly enhanced the acetylation of Ace-H3, H3K9ace, and H3K14ace. Sodium acetate-induced histone acetylation rapidly decreased upon stimulation with the calcium ionophore A23187, whereas histone citrullination markedly increased. These results demonstrate that sodium acetate induces NETosis via histone acetylation in neutrophil-like HL-60 cells, providing new insights into the therapeutic effects based on the innate immunity-enhancing effect of dietary fiber. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition)

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18 pages, 4432 KiB

Open AccessArticle

The CAMKK/AMPK Pathway Contributes to Besnoitia besnoiti-Induced NETosis in Bovine Polymorphonuclear Neutrophils

by Iván Conejeros, Zahady D. Velásquez, Lisbeth Rojas-Barón, Gabriel Espinosa, Carlos Hermosilla and Anja Taubert

Int. J. Mol. Sci. 2024, 25(15), 8442; https://doi.org/10.3390/ijms25158442 - 2 Aug 2024

Cited by 1 | Viewed by 993

Abstract

Besnoitia besnoiti is an obligate intracellular apicomplexan parasite and the causal agent of bovine besnoitiosis. Bovine besnoitiosis has a considerable economic impact in Africa and Asia due to reduced milk production, abortions, and bull infertility. In Europe, bovine besnoitiosis is classified as an emerging disease. Polymorphonuclear neutrophils (PMN) are one of the most abundant leukocytes in cattle blood and amongst the first immunological responders toward invading pathogens. In the case of B. besnoiti, bovine PMN produce reactive oxygen species (ROS), release neutrophil extracellular traps (NETs), and show increased autophagic activities upon exposure to tachyzoite stages. In that context, the general processes of NETosis and autophagy were previously reported as associated with AMP-activated protein kinase (AMPK) activation. Here, we study the role of AMPK in B. besnoiti tachyzoite-induced NET formation, thereby expanding the analysis to both upstream proteins, such as the calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK), and downstream signaling and effector molecules, such as the autophagy-related proteins ULK-1 and Beclin-1. Current data revealed early AMPK activation (<30 min) in both B. besnoiti-exposed and AMPK activator (AICAR)-treated bovine PMN. This finding correlated with upstream responses on the level of CAMKK activation. Moreover, these reactions were accompanied by an augmented autophagic activity, as represented by enhanced expression of ULK-1 but not of Beclin-1. Referring to neutrophil effector functions, AICAR treatments induced both AMPK phosphorylation and NET formation, without affecting cell viability. In B. besnoiti tachyzoite-exposed PMN, AICAR treatments failed to affect oxidative responses, but led to enhanced NET formation, thereby indicating that AMPK and autophagic activation synergize with B. besnoiti-driven NETosis. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition)

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18 pages, 3022 KiB

Open AccessArticle

Neutrophil Depletion Changes the N-Glycosylation Pattern of IgG in Experimental Murine Sepsis

by Kursat O. Yaykasli, Karin A. van Schie, René E. M. Toes, Manfred Wuhrer, Carolien A. M. Koeleman, Galyna Bila, Nazar Negrych, Georg Schett, Jasmin Knopf, Martin Herrmann and Rostyslav Bilyy

Int. J. Mol. Sci. 2024, 25(12), 6478; https://doi.org/10.3390/ijms25126478 - 12 Jun 2024

Cited by 1 | Viewed by 1387

Abstract

Sepsis is a life-threatening condition with a rising disease burden worldwide. It is a multifactorial disease and is defined as a dysregulated host response to infection. Neutrophils have been shown to be involved in the pathogenesis of sepsis by exacerbating inflammation. However, the exact effector mechanism of action still remains a mystery. Changes in the glycosylation pattern of the immunoglobulin G (IgG) Fc region are described for several diseases including meningococcal sepsis. In this study, we investigated the possible contribution of neutrophils and neutrophil implication, potentially related to degranulation or neutrophil extracellular trap (NET) formation in changing the IgG Fc N-glycosylation pattern in a murine sepsis model. We have measured the serum level of cytokines/chemokines and immunoglobulins, the serum activity of neutrophil elastase (NE), and analyzed the IgG Fc glycosylation pattern by Liquid Chromatography-Electrospray Ionization-Mass Spectrometry (LC-ESI-MS) and Lectin enzyme-linked immunosorbent assay (ELISA). We observed an increased activity of NE- and neutrophil-associated cytokines such as keratinocyte chemoattractant (KC) with the development of sepsis. Regarding the IgG Fc N-glycosylation, we observed an increase in fucosylation and α1,3-galactosylation and a decrease for sialyation. Interestingly, these changes were not uniform for all IgG subclasses. After depletion of neutrophils, we saw a change in the exposure of fucose and α2,6-linked sialic acid during the time course of our experimental sepsis model. In conclusion, neutrophils can influence changes in the IgG glycosylation pattern in experimental sepsis. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition)

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13 pages, 6032 KiB

Open AccessArticle

Extrusion of Neutrophil Extracellular Traps (NETs) Negatively Impacts Canine Sperm Functions: Implications in Reproductive Failure

by Marion León, Claudia Moya, Rodrigo Rivera-Concha, Felipe Pezo, Pamela Uribe, Mabel Schulz, Raúl Sánchez, Anja Taubert, Carlos Hermosilla and Fabiola Zambrano

Int. J. Mol. Sci. 2024, 25(11), 6216; https://doi.org/10.3390/ijms25116216 - 5 Jun 2024

Viewed by 926

Abstract

Reproductive failure in dogs is often due to unknown causes, and correct diagnosis and treatment are not always achieved. This condition is associated with various congenital and acquired etiologies that develop inflammatory processes, causing an increase in the number of leukocytes within the female reproductive tract (FRT). An encounter between polymorphonuclear neutrophils (PMNs) and infectious agents or inflammation in the FRT could trigger neutrophil extracellular traps (NETs), which are associated with significantly decreased motility and damage to sperm functional parameters in other species, including humans. This study describes the interaction between canine PMNs and spermatozoa and characterizes the release of NETs, in addition to evaluating the consequences of these structures on canine sperm function. To identify and visualize NETs, May–Grünwald Giemsa staining and immunofluorescence for neutrophil elastase (NE) were performed on canine semen samples and sperm/PMN co-cultures. Sperm viability was assessed using SYBR/PI and acrosome integrity was assessed using PNA-FITC/PI by flow cytometry. The results demonstrate NETs release in native semen samples and PMN/sperm co-cultures. In addition, NETs negatively affect canine sperm function parameters. This is the first report on the ability of NETs to efficiently entrap canine spermatozoa, and to provide additional data on the adverse effects of NETs on male gametes. Therefore, NETs formation should be considered in future studies of canine reproductive failure, as these extracellular fibers and NET-derived pro-inflammatory capacities will impede proper oocyte fertilization and embryo implantation. These data will serve as a basis to explain certain reproductive failures of dogs and provide new information about triggers and molecules involved in adverse effects of NETosis for domestic pet animals. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition)

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14 pages, 5338 KiB

Open AccessArticle

Vesicular Messages from Dental Biofilms for Neutrophils

by Ljubomir Vitkov, Jelena Krunić, Johanna Dudek, Madhusudhan Reddy Bobbili, Johannes Grillari, Bernhard Hausegger, Irena Mladenović, Nikola Stojanović, Wolf Dietrich Krautgartner, Hannah Oberthaler, Christine Schauer, Martin Herrmann, Jeeshan Singh, Bernd Minnich and Matthias Hannig

Int. J. Mol. Sci. 2024, 25(6), 3314; https://doi.org/10.3390/ijms25063314 - 14 Mar 2024

Viewed by 1647

Abstract

The encounter between dental biofilm and neutrophils in periodontitis remains elusive, although it apparently plays a crucial role in the periodontal pathology and constitutes a key topic of periodontology. Dental biofilm and neutrophils were isolated from orally healthy persons and patients with periodontitis. We investigated biofilm and its particle-shedding phenomenon with electron microscopy and nanoparticle tracking analysis (NTA); biofilm shedding–neutrophil interactions were examined ex vivo with epi-fluorescence microscopy. For this purpose, we used acellular dental biofilm shedding, purified lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA) as activators, and the interleukin 8 receptor beta (CXCR2) inhibitor and the anti-interleukin 8 receptor alpha (CXCR1) antibody as modulators. The shedding of acellular dental biofilms overwhelmingly consists of bacterial extracellular vesicles (BEVs). The latter induced the moderate formation of neutrophil extracellular traps (NETs) in orally healthy subjects and a strong formation in patients with periodontitis. A CXCR2 inhibitor and an anti-CXCR1 antibody had a minor effect on NET formation. Neutrophils from patients with periodontitis exhibited NET hyper-responsiveness. BEVs were stronger inducers of NET formation than purified LPS and PMA. A plateau of neutrophil responsiveness is reached above the age of 40 years, indicating the abrupt switch of maladaptive trained immunity (TI) into the activated modus. Our results suggest that dental biofilms consist of and disseminate immense amounts of outer membrane vesicles (OMVs), which initiate NET formation via a non-canonical cytosolic LPS/caspase-4/11/Gasdermin D pathway. This modus of NET formation is independent of neutrophil elastase (NE), myeloperoxidase (MPO), peptidylarginine deiminase 4 (PAD4), and toll-like receptors (TLR). In periodontitis, the hyper-responsiveness of neutrophils to BEVs and the increased NET formation appear to be a consequence of TI. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps (NETs) in Immunity and Diseases: 2nd Edition)

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