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Biomolecules
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Neutrophil Extracellular Trap (NET) Formation: Mechanism, Disease and Drugs
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Neutrophil Extracellular Trap (NET) Formation: Mechanism, Disease and Drugs

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 51301

Special Issue Editors

Dr. Nades Palaniyar

E-Mail Website
Guest Editor
Program in Translational Medicine, PGCRL, The Hospital for Sick Children, and Dept. of Lab Medicine and Pathobiology, and the Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Interests: AI in medicine; infectious and inflammatory diseases; neutrophil extracellular traps (NETs); molecualr mechanisms; drug scrreening
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Hans-Uwe Simon

E-Mail Website
Guest Editor
Laboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
Interests: immuno-oncology
Special Issues, Collections and Topics in MDPI journals
Dr. Victor Nizet

E-Mail
Guest Editor
Division of Host-Microbe Systems & Therapeutics, Department of Pediatrics and Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
Interests: neutrophil and macrophage function in bacterial infection; NETs; innate immune signaling; molecular pathogenesis of streptococcal and staphylococcal infections; glycobiology of host-pathogen interactions; novel approaches to treat antibiotic-resistance and sepsis including virulence factor inhibition; immune boosting and drug repurposing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extensive research work conducted over the last decade shows that neutrophils and certain other immune cells release chromatin and mitochondrial DNA coated with antimicrobial peptides and proteases as extracellular traps (NETs). NET formation is a complex process involving multiple steps, including NADPH oxidase-mediated and mitochondrial ROS production, glycolytic ATP production, activation of the cytoskeleton, kinase cascades, granular proteins coating DNA, and increases in intracellular calcium. Several studies suggest that different types of cell death could lead to NET formation (NETosis, autophagic cell death, necroptosis).

Different agonists, cell–cell interactions, external millilux, and intercellular changes regulate NET formations in various infectious, inflammatory, and autoimmune diseases. The involvement of NETs in several other diseases including cancer and cardiovascular conditions has also been reported. Relative contributions of NETs to microbial killing, compared to other tissue-specific microbicidal innate immune proteins and pathways such as complement activation, are also not fully explored. Although NETs have been considered an important antimicrobial component, it is now apparent that NETs are detrimental when formed out of context, especially during chronic inflammatory conditions.

Once NETs are released, they may be degraded by nucleases and cleared by phagocytes including macrophages. Breaking NETs with DNase I is reported to reduce tissue damage. However, suppressing excess NET formation is now considered a useful option to limit the negative effects of NETs while maintaining the phagocytic functions of neutrophils. Drugs that would regulate NET formation may hold therapeutic potential for treating NET-related diseases.

For this Special Issue, we encourage the submission of articles that describe novel mechanistic insights, NET formation agonists and antagonists, and potential drugs, for various NET-related diseases and conditions.

Dr. Nades Palaniyar
Dr. Hans-Uwe Simon
Dr. Victor Nizet
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Neutrophil extracellular traps (NETs); NETosis; ApoNETosis; necroptosis; pyroptosis; cytoplast formation
  • ET formation by other immune cells; platelets
  • molecular mechanisms; NADPH oxidase-dependent NET formation; NADPH oxidase-independent NET formation
  • Reactive oxygen and nitrogen species; kinases; histone modification; transcription; calcium-dependent Net formation; mitochondria; granular proteins; cytoskeleton; nuclear membrane
  • NET formation agonists and antagonists
  • Complement; innate immune proteins
  • NET-mediated killing
  • drugs that regulate NET formation
  • NET clearance
  • NET-mediated diseases including infection; inflammation; autoimmune diseases; nephritis; cancer; cardiovascular diseases and others

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Published Papers (4 papers)

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Research

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19 pages, 3076 KiB  
Article
Histone Deacetylase Inhibitors Dose-Dependently Switch Neutrophil Death from NETosis to Apoptosis
by Hussein J. Hamam and Nades Palaniyar
Biomolecules 2019, 9(5), 184; https://doi.org/10.3390/biom9050184 - 11 May 2019
Cited by 31 | Viewed by 4994
Abstract
Acetylation is an important post translational modification of histone that plays a role in regulation of physiological and pathological process in the body. We have recently shown that the inhibition of histone deacetylases (HDAC) by low concentrations of HDAC inhibitors (HDACis), belinostat (up [...] Read more.
Acetylation is an important post translational modification of histone that plays a role in regulation of physiological and pathological process in the body. We have recently shown that the inhibition of histone deacetylases (HDAC) by low concentrations of HDAC inhibitors (HDACis), belinostat (up to 0.25 µM) and panobinostat (up to 0.04 µM) promote histone acetylation (e.g., AcH4) and neutrophil extracellular trap formation (NETosis). Clinical use of belinostat and panobinostat often leads to neutropenia and the in vivo concentrations vary with time and tissue locations. However, the effects of different concentrations of these HDACis on neutrophil death are not fully understood. We considered that increasing concentrations of belinostat and panobinostat could alter the type of neutrophil death. To test this hypothesis, we treated human neutrophils with belinostat and panobinostat in the presence or absence of agonists that promote NOX-dependent NETosis (phorbol myristate acetate or lipopolysaccharide from Escherichia coli 0128) and NOX-independent NETosis (calcium ionophores A23187 or ionomycin from Streptomyces conglobatus). Increasing concentrations of HDACis induced histone acetylation in a dose-dependent manner. ROS analyses showed that increasing concentrations of HDACis, increased the degree of NOX-derived ROS production. Higher levels (>1 µM belinostat and >0.2 µM panobinostat) of AcH4 resulted in a significant inhibition of spontaneous as well as the NOX-dependent and -independent NETosis. By contrast, the degree of neutrophil apoptosis significantly increased, particularly in non-activated cells. Collectively, this study establishes that increasing concentrations of belinostat and panobinostat initially increases NETosis but subsequently reduces NETosis or switches the form of cell death to apoptosis. This new information indicates that belinostat and panobinostat can induce different types of neutrophil death and may induce neutropenia and regulate inflammation at different concentrations. Full article
(This article belongs to the Special Issue Neutrophil Extracellular Trap (NET) Formation: Mechanism, Disease and Drugs)
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17 pages, 2875 KiB  
Article
Histone Acetylation Promotes Neutrophil Extracellular Trap Formation
by Hussein J. Hamam, Meraj A. Khan and Nades Palaniyar
Biomolecules 2019, 9(1), 32; https://doi.org/10.3390/biom9010032 - 18 Jan 2019
Cited by 81 | Viewed by 12879
Abstract
Neutrophils undergo a unique form of cell death to generate neutrophil extracellular traps (NETs). It is well established that citrullination of histones (e.g., CitH3) facilitates chromatin decondensation during NET formation (NETosis), particularly during calcium-induced NETosis that is independent of nicotinamide adenine dinucleotide phosphate [...] Read more.
Neutrophils undergo a unique form of cell death to generate neutrophil extracellular traps (NETs). It is well established that citrullination of histones (e.g., CitH3) facilitates chromatin decondensation during NET formation (NETosis), particularly during calcium-induced NETosis that is independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation. However, the importance of other forms of histone modifications in NETosis has not been established. We considered that acetylation of histones would also facilitate NETosis. To test this hypothesis, we induced NOX-dependent NETosis in human neutrophils with phorbol myristate acetate or lipopolysaccharide (from Escherichia coli 0128), and NOX-independent NETosis with calcium ionophores A23187 or ionomycin (from Streptomyces conglobatus) in the presence or absence of two pan histone deacetylase inhibitors (HDACis), belinostat and panobinostat (within their half maximal inhibitory concentration (IC50) range). The presence of these inhibitors increased histone acetylation (e.g., AcH4) in neutrophils. Histone acetylation was sufficient to cause a significant increase (~20%) in NETosis in resting neutrophils above baseline values. When acetylation was promoted during NOX-dependent or -independent NETosis, the degree of NETosis additively increased (~15–30%). Reactive oxygen species (ROS) production is essential for baseline NETosis (mediated either by NOX or mitochondria); however, HDACis did not promote ROS production. The chromatin decondensation step requires promoter melting and transcriptional firing in both types of NETosis; consistent with this point, suppression of transcription prevented the NETosis induced by the acetylation of histones. Collectively, this study establishes that histone acetylation (e.g., AcH4) promotes NETosis at baseline, and when induced by both NOX-dependent or -independent pathway agonists, in human neutrophils. Therefore, we propose that acetylation of histone is a key component of NETosis. Full article
(This article belongs to the Special Issue Neutrophil Extracellular Trap (NET) Formation: Mechanism, Disease and Drugs)
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Review

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25 pages, 1703 KiB  
Review
Post-Translational Modifications in NETosis and NETs-Mediated Diseases
by Hussein J. Hamam and Nades Palaniyar
Biomolecules 2019, 9(8), 369; https://doi.org/10.3390/biom9080369 - 14 Aug 2019
Cited by 76 | Viewed by 16262
Abstract
Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the [...] Read more.
Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the mechanistic details of the different forms of NETosis and their common end structure, as NETs were constantly found to contain DNA, modified histones and cytotoxic enzymes. In fact, emerging evidence reveal that the post translational modifications (PTMs) of histones in neutrophils have a critical role in regulating neutrophil death. Histone citrullination is shown to promote a rapid form of NET formation independent of NADPH oxidase (NOX), which relies on calcium influx. Interestingly, few studies suggest an association between histone citrullination and other types of PTMs to control cell survival and death, such as histone methylation. Even more exciting is the finding that histone acetylation has a biphasic effect upon NETosis, where histone deacetylase (HDAC) inhibitors promote baseline, NOX-dependent and -independent NETosis. However, increasing levels of histone acetylation suppresses NETosis, and to switch neutrophil death to apoptosis. Interestingly, in the presence of NETosis-promoting stimuli, high levels of HDACis limit both NETosis and apoptosis, and promote neutrophil survival. Recent studies also reveal the importance of the PTMs of neutrophils in influencing numerous pathologies. Histone modifications in NETs can act as a double-edged sword, as they are capable of altering multiple types of neutrophil death, and influencing numerous NET-mediated diseases, such as acute lung injury (ALI), thrombosis, sepsis, systemic lupus erythematosus, and cancer progression. A clear understanding of the role of different PTMs in neutrophils would be important for an understanding of the molecular mechanisms of NETosis, and to appropriately treat NETs-mediated diseases. Full article
(This article belongs to the Special Issue Neutrophil Extracellular Trap (NET) Formation: Mechanism, Disease and Drugs)
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15 pages, 624 KiB  
Review
Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology
by Mithunan Ravindran, Meraj A. Khan and Nades Palaniyar
Biomolecules 2019, 9(8), 365; https://doi.org/10.3390/biom9080365 - 14 Aug 2019
Cited by 194 | Viewed by 15744
Abstract
Neutrophil extracellular traps (NETs), a unique DNA framework decorated with antimicrobial peptides, have been in the scientific limelight for their role in a variety of pathologies ranging from cystic fibrosis to cancer. The formation of NETs, as well as relevant regulatory mechanisms, physiological [...] Read more.
Neutrophil extracellular traps (NETs), a unique DNA framework decorated with antimicrobial peptides, have been in the scientific limelight for their role in a variety of pathologies ranging from cystic fibrosis to cancer. The formation of NETs, as well as relevant regulatory mechanisms, physiological factors, and pharmacological agents have not been systematically discussed in the context of their beneficial and pathological aspects. Novel forms of NET formation including vital NET formation continue to be uncovered, however, there remain fundamental questions around established mechanisms such as NADPH-oxidase (Nox)-dependent and Nox-independent NET formation. Whether NET formation takes place in the tissue versus the bloodstream, internal factors (e.g. reactive oxygen species (ROS) production and transcription factor activation), and external factors (e.g. alkaline pH and hypertonic conditions), have all been demonstrated to influence specific NET pathways. Elements of neutrophil biology such as transcription and mitochondria, which were previously of unknown significance, have been identified as critical mediators of NET formation through facilitating chromatin decondensation and generating ROS, respectively. While promising therapeutics inhibiting ROS, transcription, and gasdermin D are being investigated, neutrophil phagocytosis plays a critical role in host defense and any therapies targeting NET formation must avoid impairing the physiological functions of these cells. This review summarizes what is known in the many domains of NET research, highlights the most relevant challenges in the field, and inspires new questions that can bring us closer to a unified model of NET formation. Full article
(This article belongs to the Special Issue Neutrophil Extracellular Trap (NET) Formation: Mechanism, Disease and Drugs)
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