Editorial

4 pages, 194 KiB

Open AccessEditorial

Neutrophils and Neutrophil Extracellular Traps Regulate Immune Responses in Health and Disease

by Shrikant R. Mulay and Hans-Joachim Anders

Cells 2020, 9(9), 2130; https://doi.org/10.3390/cells9092130 - 20 Sep 2020

Cited by 12 | Viewed by 2772

Neutrophils are first responders of antimicrobial host defense and sterile inflammation, and therefore, play important roles during health and disease [...] Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

Research

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19 pages, 7876 KiB

Open AccessArticle

Neutrophil Chemotaxis and NETosis in Murine Chronic Liver Injury via Cannabinoid Receptor 1/Gα_i/o/ROS/p38 MAPK Signaling Pathway

by Xuan Zhou, Le Yang, Xiaoting Fan, Xinhao Zhao, Na Chang, Lin Yang and Liying Li

Cells 2020, 9(2), 373; https://doi.org/10.3390/cells9020373 - 05 Feb 2020

Cited by 24 | Viewed by 5596

Abstract

Neutrophils play an essential role in the control of inflammatory diseases. However, whether cannabinoid receptors (CBs) play a role in neutrophil chemotaxis and NETosis in sterile liver inflammation remains unknown. The expression of marker genes on neutrophils was characterized by FACS, immunofluorescence, qRT-PCR, [...] Read more.

Neutrophils play an essential role in the control of inflammatory diseases. However, whether cannabinoid receptors (CBs) play a role in neutrophil chemotaxis and NETosis in sterile liver inflammation remains unknown. The expression of marker genes on neutrophils was characterized by FACS, immunofluorescence, qRT-PCR, and Western blot. The amount of neutrophils was significantly elevated from 7 days and reached the peak at 2 weeks in carbon tetrachloride (CCl₄)-treated mouse liver. The mRNA expression of neutrophil marker Ly6G had positive correlation with CB1 and CB2 expression in injured liver. In vitro CBs were abundantly expressed in isolated neutrophils and CB1 agonist ACEA promoted the chemotaxis and cytoskeletal remodeling, which can be suppressed by CB1 antagonist AM281. Moreover, ACEA induced NETosis, myeloperoxidase release from lysosome and ROS burst, indicating neutrophil activation, via Gα_i/o. Conversely, CB2 agonist JWH133 had no effect on neutrophil function. ROS and p38 MAPK signaling pathways were involved in CB1-mediated neutrophil function, and ROS was upstream of p38 MAPK. CB1 blockade in vivo significantly attenuated neutrophil infiltration and liver inflammation in CCl₄-treated mice. Taken together, CB1 mediates neutrophil chemotaxis and NETosis via Gα_i/o/ROS/p38 MAPK signaling pathway in liver inflammation, which represents an effective therapeutic strategy for liver diseases. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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14 pages, 5951 KiB

Open AccessArticle

Plasma Proteins and Platelets Modulate Neutrophil Clearance of Malaria-Related Hemozoin Crystals

by Sueli de Oliveira Silva Lautenschlager, Tehyung Kim, Danielle Lazarim Bidóia, Celso Vataru Nakamura, Hans-Joachim Anders and Stefanie Steiger

Cells 2020, 9(1), 93; https://doi.org/10.3390/cells9010093 - 30 Dec 2019

Cited by 12 | Viewed by 4103

Abstract

Hemozoin is an insoluble crystalline pigment produced by the malaria parasite Plasmodia upon digesting host hemoglobin inside red blood cells. Red blood cell rupture releases hemozoin crystals into the circulation from where they are cleared by phagocytes such as neutrophils. We speculated that [...] Read more.

Hemozoin is an insoluble crystalline pigment produced by the malaria parasite Plasmodia upon digesting host hemoglobin inside red blood cells. Red blood cell rupture releases hemozoin crystals into the circulation from where they are cleared by phagocytes such as neutrophils. We speculated that plasma proteins would affect the ability of neutrophils to clear hemozoin crystals. To test this, we cultured human blood neutrophils with hemozoin ex vivo and found that neutrophils ingested hemozoin (0.1–1 µm crystal size) in a dose-dependent manner into phagosomes and vesicles/vacuoles, resulting in morphological changes including nuclear enlargement, and vesicle formation, but not cell membrane rupture or release of neutrophil extracellular traps. The presence of human plasma significantly inhibited the ability of neutrophils to ingest hemozoin crystals. Platelet-poor plasma further inhibited the uptake of hemozoin by neutrophils. Selective exposure to fibrinogen completely replicated the plasma effect. Taken together, neutrophils cleared hemozoin crystals from the extracellular space via endocytosis into phagosomes and vesicles without inducing the release of neutrophil extracellular traps. However, human plasma components such as fibrinogen limited hemozoin clearance, whereas the presence of platelets augmented this process. These factors may influence the pro-inflammatory potential of hemozoin crystals in malaria. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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14 pages, 1036 KiB

Open AccessArticle

Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections

by Daniel Appelgren, Helena Enocsson, Barbro H. Skogman, Marika Nordberg, Linda Perander, Dag Nyman, Clara Nyberg, Jasmin Knopf, Luis E. Muñoz, Christopher Sjöwall and Johanna Sjöwall

Cells 2020, 9(1), 43; https://doi.org/10.3390/cells9010043 - 23 Dec 2019

Cited by 22 | Viewed by 4090

Abstract

Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the [...] Read more.

Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (r_s = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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17 pages, 3584 KiB

Open AccessArticle

Farnesol, a Quorum-Sensing Molecule of Candida albicans Triggers the Release of Neutrophil Extracellular Traps

by Marcin Zawrotniak, Karolina Wojtalik and Maria Rapala-Kozik

Cells 2019, 8(12), 1611; https://doi.org/10.3390/cells8121611 - 11 Dec 2019

Cited by 33 | Viewed by 4336

Abstract

The efficient growth of pathogenic bacteria and fungi in the host organism is possible due to the formation of microbial biofilms that cover the host tissues. Biofilms provide optimal local environmental conditions for fungal cell growth and increased their protection against the immune [...] Read more.

The efficient growth of pathogenic bacteria and fungi in the host organism is possible due to the formation of microbial biofilms that cover the host tissues. Biofilms provide optimal local environmental conditions for fungal cell growth and increased their protection against the immune system. A common biofilm-forming fungus—Candida albicans—uses the quorum sensing (QS) mechanism in the cell-to-cell communication, which determines the biofilm development and, in consequence, host colonization. In the presented work, we focused on the ability of neutrophils—the main cells of the host’s immune system to recognize quorum sensing molecules (QSMs) produced by C. albicans, especially farnesol (FOH), farnesoic acid (FA), and tyrosol (TR), with emphasis on the neutrophil extracellular traps (NETs) formation in a process called netosis. Our results showed for the first time that only farnesol but not farnesolic acid or tyrosol is capable of activating the NET production. By using selective inhibitors of the NET signaling pathway and analyzing the activity of selected enzymes such as Protein Kinase C (PKC), ERK1/2, and NADPH oxidase, we showed that the Mac−1 and TLR2 receptors are responsible for FOH recognizing and activating the reactive oxygen species (ROS)-dependent netosis pathway. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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22 pages, 4870 KiB

Open AccessArticle

Neutrophil Extracellular Traps in the Pathogenesis of Equine Recurrent Uveitis (ERU)

by Leonie Fingerhut, Bernhard Ohnesorge, Myriam von Borstel, Ariane Schumski, Katrin Strutzberg-Minder, Matthias Mörgelin, Cornelia A. Deeg, Henk P. Haagsman, Andreas Beineke, Maren von Köckritz-Blickwede and Nicole de Buhr

Cells 2019, 8(12), 1528; https://doi.org/10.3390/cells8121528 - 27 Nov 2019

Cited by 22 | Viewed by 3541

Abstract

Equine recurrent uveitis (ERU) is considered one of the most important eye diseases in horses and typically appears with relapsing inflammatory episodes without systemic effects. Various disorders have been described as an initial trigger, including infections. Independent of the initiating cause, there are [...] Read more.

Equine recurrent uveitis (ERU) is considered one of the most important eye diseases in horses and typically appears with relapsing inflammatory episodes without systemic effects. Various disorders have been described as an initial trigger, including infections. Independent of the initiating cause, there are numerous indications that ERU is an immune-mediated disease. We investigated whether neutrophil extracellular traps (NETs) are part of the ERU pathogenesis. Therefore, vitreous body fluids (VBF), sera, and histological sections of the eye from ERU-diseased horses were analyzed for the presence of NET markers and compared with horses with healthy eyes. In addition, NET formation by blood derived neutrophils was investigated in the presence of VBF derived from horses with healthy eyes versus ERU-diseased horses using immunofluorescence microscopy. Interestingly, NET markers like free DNA, histone-complexes, and myeloperoxidase were detected in higher amounts in samples from ERU-diseased horses. Furthermore, in vitro NET formation was higher in neutrophils incubated with VBF from diseased horses compared with those animals with healthy eyes. Finally, we characterized the ability of equine cathelicidins to induce NETs, as potential NET inducing factors in ERU-diseased horses. In summary, our findings lead to the hypothesis that ERU-diseased horses develop more NETs and that these may contribute to the pathogenesis of ERU. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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15 pages, 5214 KiB

Open AccessArticle

Prognostic Role of Blood NETosis in the Progression of Head and Neck Cancer

by Anna Sophie Decker, Ekaterina Pylaeva, Alexandra Brenzel, Ilona Spyra, Freya Droege, Timon Hussain, Stephan Lang and Jadwiga Jablonska

Cells 2019, 8(9), 946; https://doi.org/10.3390/cells8090946 - 21 Aug 2019

Cited by 35 | Viewed by 6137

Abstract

Neutrophil extracellular traps (NETs) represent web-like structures consisting of externalized DNA decorated with granule proteins that are responsible for trapping and killing bacteria. However, undesirable effects of NET formation during carcinogenesis, such as metastasis support, have been described. In the present study, we [...] Read more.

Neutrophil extracellular traps (NETs) represent web-like structures consisting of externalized DNA decorated with granule proteins that are responsible for trapping and killing bacteria. However, undesirable effects of NET formation during carcinogenesis, such as metastasis support, have been described. In the present study, we evaluated the correlation between NETosis and disease progression in head and neck cancer (HNC) patients in order to establish a valid biomarker for an early detection and monitoring of HNC progression. Moreover, factors influencing NET release in HNC patients were revealed. We showed a significantly elevated vital NETosis in neutrophils isolated from early T1–T2 and N0–N2 stage patients, as compared to healthy controls. Additionally, in our experimental setting, we confirmed the involvement of tumor cells in the stimulation of NET formation. Interestingly, in advanced cancer stages (T3–4, N3) NETosis was reduced. This also correlated with the levels of granulocyte colony-stimulating factor (G-CSF) in plasma and tumor tissue. Altogether, we suggest that the elevated NETosis in blood can be used as a biomarker to detect early HNC and to predict patients at risk to develop tumor metastasis. Therapeutic disruption of NET formation may offer new roads for successful treatment of HNC patients in order to prevent metastasis. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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Review

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18 pages, 1972 KiB

Open AccessReview

Neutrophil Extracellular Traps in Periodontitis

by Antonio Magán-Fernández, Sarmad Muayad Rasheed Al-Bakri, Francisco O’Valle, Cristina Benavides-Reyes, Francisco Abadía-Molina and Francisco Mesa

Cells 2020, 9(6), 1494; https://doi.org/10.3390/cells9061494 - 19 Jun 2020

Cited by 42 | Viewed by 5364

Abstract

Neutrophils are key cells of the immune system and have a decisive role in fighting foreign pathogens in infectious diseases. Neutrophil extracellular traps (NETs) consist of a mesh of DNA enclosing antimicrobial peptides and histones that are released into extracellular space following neutrophil [...] Read more.

Neutrophils are key cells of the immune system and have a decisive role in fighting foreign pathogens in infectious diseases. Neutrophil extracellular traps (NETs) consist of a mesh of DNA enclosing antimicrobial peptides and histones that are released into extracellular space following neutrophil response to a wide range of stimuli, such as pathogens, host-derived mediators and drugs. Neutrophils can remain functional after NET formation and are important for periodontal homeostasis. Periodontitis is an inflammatory multifactorial disease caused by a dysbiosis state between the gingival microbiome and the immune response of the host. The pathogenesis of periodontitis includes an immune-inflammatory component in which impaired NET formation and/or elimination can be involved, contributing to an exacerbated inflammatory reaction and to the destruction of gingival tissue. In this review, we summarize the current knowledge about the role of NETs in the pathogenesis of periodontitis. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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20 pages, 815 KiB

Open AccessFeature PaperReview

Neutrophil Extracellular Traps (NETs) Take the Central Stage in Driving Autoimmune Responses

by Esther Fousert, René Toes and Jyaysi Desai

Cells 2020, 9(4), 915; https://doi.org/10.3390/cells9040915 - 08 Apr 2020

Cited by 146 | Viewed by 11081

Abstract

Following fifteen years of research, neutrophil extracellular traps (NETs) are widely reported in a large range of inflammatory infectious and non-infectious diseases. Cumulating evidences from in vitro, in vivo and clinical diagnostics suggest that NETs may play a crucial role in inflammation and [...] Read more.

Following fifteen years of research, neutrophil extracellular traps (NETs) are widely reported in a large range of inflammatory infectious and non-infectious diseases. Cumulating evidences from in vitro, in vivo and clinical diagnostics suggest that NETs may play a crucial role in inflammation and autoimmunity in a variety of autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Most likely, NETs contribute to breaking self-tolerance in autoimmune diseases in several ways. During this review, we discuss the current knowledge on how NETs could drive autoimmune responses. NETs can break self-tolerance by being a source of autoantigens for autoantibodies found in autoimmune diseases, such as anti-citrullinated protein antibodies (ACPAs) in RA, anti-dsDNA in SLE and anti-myeloperoxidase and anti-protein 3 in AAV. Moreover, NET components could accelerate the inflammatory response by mediating complement activation, acting as danger-associated molecular patterns (DAMPs) and inflammasome activators, for example. NETs also can activate other immune cells, such as B cells, antigen-presenting cells and T cells. Additionally, impaired clearance of NETs in autoimmune diseases prolongs the presence of active NETs and their components and, in this way, accelerate immune responses. NETs have not only been implicated as drivers of inflammation, but also are linked to resolution of inflammation. Therefore, NETs may be central regulators of inflammation and autoimmunity, serve as biomarkers, as well as promising targets for future therapeutics of inflammatory autoimmune diseases. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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17 pages, 1591 KiB

Open AccessReview

Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update

by Aldo Bonaventura, Alessandra Vecchié, Antonio Abbate and Fabrizio Montecucco

Cells 2020, 9(1), 231; https://doi.org/10.3390/cells9010231 - 17 Jan 2020

Cited by 106 | Viewed by 12713

Abstract

Neutrophil extracellular traps (NETs) are formed by decondensed chromatin, histones, and neutrophil granular proteins and have a role in entrapping microbial pathogens. NETs, however, have pro-thrombotic properties by stimulating fibrin deposition, and increased NET levels correlate with larger infarct size and predict major [...] Read more.

Neutrophil extracellular traps (NETs) are formed by decondensed chromatin, histones, and neutrophil granular proteins and have a role in entrapping microbial pathogens. NETs, however, have pro-thrombotic properties by stimulating fibrin deposition, and increased NET levels correlate with larger infarct size and predict major adverse cardiovascular (CV) events. NETs have been involved also in the pathogenesis of diabetes, as high glucose levels were found to induce NETosis. Accordingly, NETs have been described as drivers of diabetic complications, such as diabetic wound and diabetic retinopathy. Inflammasomes are macromolecular structures involved in the release of pro-inflammatory mediators, such as interleukin-1, which is a key mediator in CV diseases. A crosstalk between the inflammasome and NETs is known for some rheumatologic diseases, while this link is still under investigation and not completely understood in CV diseases. In this review, we summarized the most recent updates about the role of NETs in acute myocardial infarction and metabolic diseases and provided an overview on the relationship between NET and inflammasome activities in rheumatologic diseases, speculating a possible link between these two entities also in CV diseases. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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Graphical abstract

14 pages, 1325 KiB

Open AccessReview

The Brain Entangled: The Contribution of Neutrophil Extracellular Traps to the Diseases of the Central Nervous System

by Aneta Manda-Handzlik and Urszula Demkow

Cells 2019, 8(12), 1477; https://doi.org/10.3390/cells8121477 - 21 Nov 2019

Cited by 94 | Viewed by 6529

Abstract

Under normal conditions, neutrophils are restricted from trafficking into the brain parenchyma and cerebrospinal fluid by the presence of the brain–blood barrier (BBB). Yet, infiltration of the central nervous system (CNS) by neutrophils is a well-known phenomenon in the course of different pathological [...] Read more.

Under normal conditions, neutrophils are restricted from trafficking into the brain parenchyma and cerebrospinal fluid by the presence of the brain–blood barrier (BBB). Yet, infiltration of the central nervous system (CNS) by neutrophils is a well-known phenomenon in the course of different pathological conditions, e.g., infection, trauma or neurodegeneration. Different studies have shown that neutrophil products, i.e., free oxygen radicals and proteolytic enzymes, play an important role in the pathogenesis of BBB damage. It was recently observed that accumulating granulocytes may release neutrophil extracellular traps (NETs), which damage the BBB and directly injure surrounding neurons. In this review, we discuss the emerging role of NETs in various pathological conditions affecting the CNS. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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16 pages, 588 KiB

Open AccessReview

Neutrophil Extracellular Traps: Current Perspectives in the Eye

by Gibrán Alejandro Estúa-Acosta, Rocío Zamora-Ortiz, Beatriz Buentello-Volante, Mariana García-Mejía and Yonathan Garfias

Cells 2019, 8(9), 979; https://doi.org/10.3390/cells8090979 - 27 Aug 2019

Cited by 27 | Viewed by 7446

Abstract

Neutrophil extracellular traps (NETs) have been the subject of research in the field of innate immunity since their first description more than a decade ago. Neutrophils are the first cells recruited at sites of inflammation, where they perform their specific functions, including the [...] Read more.

Neutrophil extracellular traps (NETs) have been the subject of research in the field of innate immunity since their first description more than a decade ago. Neutrophils are the first cells recruited at sites of inflammation, where they perform their specific functions, including the release of NETs, which consist of web-like structures composed of granule proteins bound to decondensed chromatin fibres. This process has aroused interest, as it contributes to understanding how pathogenic microorganisms are contained, but they are also associated with pathophysiological processes of a wide range of diseases. Currently, there are growing reports of new molecules involved in the formation and release of NETs. However, whether the release of NETs contributes to eye diseases remains unclear. For this reason, the overall aim of this review is to gather current data of recent research in the ophthalmology field, where there is still much to discover. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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Other

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8 pages, 611 KiB

Open AccessPerspective

Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19

by Bhawna Tomar, Hans-Joachim Anders, Jyaysi Desai and Shrikant R. Mulay

Cells 2020, 9(6), 1383; https://doi.org/10.3390/cells9061383 - 02 Jun 2020

Cited by 198 | Viewed by 10242

Abstract

The COVID-19 pandemic is progressing worldwide with an alarming death toll. There is an urgent need for novel therapeutic strategies to combat potentially fatal complications. Distinctive clinical features of severe COVID-19 include acute respiratory distress syndrome, neutrophilia, and cytokine storm, along with severe [...] Read more.

The COVID-19 pandemic is progressing worldwide with an alarming death toll. There is an urgent need for novel therapeutic strategies to combat potentially fatal complications. Distinctive clinical features of severe COVID-19 include acute respiratory distress syndrome, neutrophilia, and cytokine storm, along with severe inflammatory response syndrome or sepsis. Here, we propose the putative role of enhanced neutrophil infiltration and the release of neutrophil extracellular traps, complement activation and vascular thrombosis during necroinflammation in COVID-19. Furthermore, we discuss how neutrophilic inflammation contributes to the higher mortality of COVID-19 in patients with underlying co-morbidities such as diabetes and cardiovascular diseases. This perspective highlights neutrophils as a putative target for the immunopathologic complications of severely ill COVID-19 patients. Development of the novel therapeutic strategies targeting neutrophils may help reduce the overall disease fatality rate of COVID-19. Full article

(This article belongs to the Special Issue Neutrophil Extracellular Traps: Mechanisms and Role in Health and Disease)

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