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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 82-87

New insights in neutrophil extracellular traps: Its possible association in COVID-19 pathogenesis


Department of Periodontics, Himachal Dental College, Sundernagar, Himachal Pradesh, India

Date of Submission12-Jul-2020
Date of Decision23-Jul-2020
Date of Acceptance16-Aug-2020
Date of Web Publication28-Jan-2021

Correspondence Address:
Dr. Pallavi Sharma
Department of Periodontics, Himachal Dental College, Sundernagar - 175 002, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sidj.sidj_26_20

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  Abstract 

Neutrophils discovered by Elie Metchnikoff are granulocytes that play a critical role as a first-line defense in innate immunity. They freely circulate in the blood vessels. Upon receiving the chemotactic gradient signal, neutrophils become the first white blood cells that get activated in various inflammatory sites, defending the human body from the microbial attack. The process of neutrophil extracellular traps (NETs) formation, through the neutrophil action mechanism, is a specific type of cell death, known as NETosis, distinct from necrosis and apoptosis. Oxidative burst mechanisms kill the pathogens trapped in NETs by two procedures – production of reactive oxygen species and chromatin unfolding. The mechanism of NETs draws an analog with the pathogenesis of periodontitis due to dysregulated neutrophilic response to specific bacterial species found in subgingival plaque. NETs are a fibrous structure that consists of a backbone of chromatin with attached globular domains. There are granular proteins and peptides in these domains as well as some cytoplasmic components. The core histones-A potent antimicrobials (H2A, H2B, H3, and H4) that together account for around 70% of the protein mass are the key component of the system. In this NETs-novel coronavirus disease-19 (nCOVID-19) intriguing centric overview, we have a mechanism for NET production; the ability of NETs to entrap and kill pathogens, including the potential immunogenicity of NETs in disease. We have also speculated a few comments on the possible role of NETs in the nCOVID-19.

Keywords: Acute respiratory distress syndrome, COVID-19, neutrophil extracellular traps, neutrophils


How to cite this article:
Fanda K, Sharma P, Jindal V, Malhotra R, Goel A, Thakur M, Vashisht S. New insights in neutrophil extracellular traps: Its possible association in COVID-19 pathogenesis. Saint Int Dent J 2020;4:82-7

How to cite this URL:
Fanda K, Sharma P, Jindal V, Malhotra R, Goel A, Thakur M, Vashisht S. New insights in neutrophil extracellular traps: Its possible association in COVID-19 pathogenesis. Saint Int Dent J [serial online] 2020 [cited 2021 Jun 14];4:82-7. Available from: https://www.sidj.org/text.asp?2020/4/2/82/308173


  Introduction Top


Neutrophils are the most copious type of granulocytes contains a hundred types of proteins, including bacterial proteins such as α-defensins, the cathelicidin human cationic antimicrobial protein 18 found in the peripheral circulation of the human body. During acute inflammation, neutrophils circulating in the bloodstream get deployed to the site of infection following adhesion, rolling, diapedesis, and chemotaxis. Following the chemotactic signals, neutrophils reach the inflammatory site, and there through various mechanisms destroy the pathogens. These mechanisms can include phagocytosis, degranulation, and the recently discovered formation of extracellular traps.[1]

The key role of neutrophil extracellular traps (NETs) is trapping, and killing various pathogens include bacteria, fungi, protozoa, and viruses.[1] Few hypothetical published facts have attempted to uncover the association between NETs and severe acute respiratory syndrome novel coronavirus-2 (SARS-nCoV-2) viral infection.

In December 2019, the world witnessed the emergence of novel SARS-CoV-2, widely known as novel coronavirus disease-19 (nCOVID-19), an acute respiratory syndrome. The symptoms appear gradually with headache, muscle pain, fatigue/tiredness, fever, cough, loss of taste sensation, diarrhea, and shortness of breath. The acute lung injury/acute respiratory distress syndrome (ALI/ARDS), commonly seen in nCOVID-19 patients, is a disorder of acute inflammation disrupting the lung endothelial and epithelial barriers. Cellular characteristics of ALI include loss of alveolar-capillary membrane integrity, excessive transepithelial neutrophil migration, and release of pro-inflammatory cytotoxic mediators.[2] Various studies have already established a possible connection between ARDS/ALI and nCOVID-19. nCOVID-19 patients are also generally found to have hyperinflammation of lung as well as multiorgan failures. The mechanisms that cause excessive inflammation of lungs following SARS-nCov-2 infection are still under research, but growing recent studies and published kinds of literature have pointed toward NETs as one of its causes.

After studying some of the printed facts in this intriguing review article, we have focused on some standard links between COVID-19 pathogenesis and NET dysregulation while offering an outline of the NET formation, function, and pathogenic dysregulation.


  Netosis Top


NETosis is the release of NETs from the matured neutrophils through a molecular signaling mechanism. Fuchs et al. stated that NETs were produced during a process of programmed cell death different from apoptosis (no DNA fragmentation and in morphological characters) and necrosis (morphological change in the nucleus). They termed it as NETosis.[3] NETs are released as the cell membrane breaks under the influence of various pathogens such as bacteria, fungi, viruses, and protozoa along with the number of host factors such as activated platelets or any inflammatory stimuli or chemical compounds such as phorbol-12-myristate-13-acetate.[4] NETs, as the name suggests, just like a trap grab, neutralize and kill the pathogens preventing their dissemination. They act as a double-edge – helping in removing the pathogens, but if dysregulated, they can contribute to the pathogenesis of immune-related diseases.


  Molecular Basis of Neutrophil Extracellular Traps Formation Top


The production of extra cell traps begins with the loss of strong organizational nuclei structure inactive cells followed by chromatin decondensation. The distinctive nuclei form, resulting in a gap arising between the nucleus inner and outer membrane, contributing to the widespread destruction of the membrane. Around the same time, granular membrane disintegrates through the cell's cytoplasm, which allows the infection of granular content with chromatin leakage through the cytoplasm into the broken cell membrane. Eventually, the cell membrane explosion occurs, and the DNA is released through the extracellular matrix in tandem with the granular material.


  Activation Pathway Top


The activation pathway is still under research but is thought to begin with NADPH oxidase activation of protein-arginine deiminase 4 (PAD4) via reactive oxygen species (ROS). Further, PAD4 enables the citrullination of histones in the neutrophils, which can decondense the chromatin. Meanwhile, primary or azurophilic granule proteins such as myeloperoxidase (MPO) and neutrophil elastase (NE) enter the nucleus, aggravating the decondensation process, which leads to the nuclear envelope rupture. So far, two distinct forms of NETosis have been identified which are:

  • A type of cell death pathway of chromatin decondensation, nuclear and cytoplasmic disintegration, followed by the expulsion of the chromatin and granular contents into extracellular space [Figure 1][5]
  • The second form of NETosis involves the ejection of DNA serine proteases from intact neutrophils and also mitochondrial DNA release that works by activating inflammation and is not associated with cell death.
Figure 1: Neutrophil extracellular traps (NETs) are formed when neutrophils release decondensed chromatin decorated with antimicrobial molecules, into the extracellular space. ROS: Reactive oxygen species[5]

Click here to view


The uncondensed chromatin enters the cytoplasm, where the additional granule and cytoplasmic proteins are added to the NET.[6] Now, the release of NET depends on two ways:

  1. Suicidal NETosis
  2. Vital/nonlytic NETosis.


Suicidal NETosis

Also known as beneficial/vital suicide NETosis, conventional suicidal NETosis was first described in 2007 by Fuchs et al. They noted that the release of NETs is due to programmed cell death, which was different from apoptosis and necrosis.[3] In suicidal NETosis, the intracellular NET formation is followed by plasma membrane rupture and releasing it into the extracellular space. This pathway can be initiated and triggered by IgG-Fc receptors by activating toll-like receptors (TLRs) and complement or cytokine receptors with various ligands such as antibodies and phorbol myristate acetate.[6] These receptors got activated upon stimulation from ligands and sequestrated calcium inside endoplasmic reticulum, which results in the release of calcium ions after this increase in protein kinase and phosphorylation (gp91phox) occurs known as a phagocytic oxidase. And hence, successive generation of ROS occurs. Calcium then activates NADPH oxidase, resulting in the activation of the NETosis pathway [Figure 1].[7]

Vital nonlytic NETosis

Pilsczek et al. in 2010 described an alternative mechanism of NETosis in response to the exposure to Staphylococcus aureus, which did not require neutrophil lysis or even the breach of the plasma membrane.[8] During this process, neutrophils can maintain their integrity and live cell functions, such as migration and phagocytosis, are triggered by complement-opsonized targets that occur more rapidly within a period of 30 min. This form takes place within minutes of stimulation of neutrophils by bacterial lipopolysaccharide (LPS), TLR4-activated platelets, or complement proteins with TLR2 ligands. In this pathway, there is blebbing of the nucleus, resulting in a DNA-filled vesicle that is exocytosed and leaves the plasma membrane intact.[6]


  Neutrophil Extracellular Traps: A Double-Edge Sword Top


NETs can be both fruitful and harmful. They have the potential to capture and destroy the pathogenic microorganisms and if dysregulated, it can have adverse consequences on the immune response on the host, leading to various immune-related diseases. The unbalanced NET formation is associated with pathological conditions such as respiratory distress (ALI/ARDS), autoimmune diseases (systemic lupus erythematosus and small-vessel vasculitis), and thrombosis. It can also be involved with metastasis.[1]

Beneficial innate response

NETs have a positive antimicrobial role, thus helping in the innate immunity of the individual. The original structure of NETs allows capturing a wide variety of microorganisms such as bacteria (S. aureus), fungi (Candida albicans, Aspergillus sp.), protozoa (Toxoplasma gondii), and viruses (HIV).

We have concentrated more on viral response of NET, viral pathogenesis, and respiratory illnesses to establish the possible link between NETs and COVID-19.

Antiviral response

Evidence suggests that neutrophils play a vital role in antiviral immune responses. In vitro studies have indicated that viruses can directly stimulate neutrophils to produce low levels of NETs.[9] NETosis is also triggered by the pro-inflammatory cytokines and chemokines such as interleukin (IL-8) produced by virus-infected endothelia and epithelia. Furthermore, NET components can contribute to antiviral immunity by stimulating other immune cells to release pro-inflammatory cytokines and chemokines. Type I interferon (IFN) can be seen in abundance during viral infections and that primes neutrophils to form NETs. Evidence suggested that platelets are essential for defense against viruses. Activated platelets aggregate with neutrophils and thereby stimulate NETosis.[9]

There are many direct mechanisms also by which NETs develop antiviral immunity. First of all, the web-like chromatin of NETs can attract and then immobilize the viral particles due to the attraction between positively charged histones and negatively charged viral envelope. This helps in preventing viral multiplication, secondly by antimicrobial molecules such as MPO, cathelicidins, and alpha-defensins, getting attached to NETs and inactivating viral particles. Thirdly, NETs release large amounts of Type I IFN, playing a pivotal role in antiviral immunity. NETs can be enriched in mitochondrial DNA, which further promotes more Type I IFN production.[10]

Neutrophil extracellular traps and viral pathogenesis

While contributing to the antiviral immunity, NETosis may also result in immunopathology. Impaired degradation and clearance of NET may result in its overflow in the circulation in detectable amounts. This systemic NET overflow has severe direct and indirect adverse effects. Systemic NET overflow may result from clearance deficiency or increased NET production. Transient systemic NET overflow due to increased NET formation without noticeable deficiency in DNase activity can occur during infection with hantaviruses.[9] Neutrophils play an antiviral role during viral hemorrhagic fevers caused by hantaviruses. In humans, they can induce severe pulmonary and renal dysfunction as well as intravascular coagulation and hemorrhagic shock. High levels of circulating NETs, and accordingly increased amounts of rDNA and histones, are detected in hantavirus-infected patients. NETs can induce autoantibodies that may contribute to the systemic pathology of the hantavirus-associated disease. Neutrophils can detect HIV-1 via interaction with TLRs (TLR7 and TLR8).[10],[11] These TLRs recognize viral nucleic acids and induce the generation of ROS by MPO-derived oxidants that trigger the NETs formation and elimination of HIV-1. Furthermore, NETs and neutrophils are involved in chikungunya virus pathologies, simian immunodeficiency virus, influenza, parvovirus, rhinovirus, and influenza pneumonia.[10]


  Neutrophil Extracellular Traps and Lung Diseases Top


Chronic lung inflammation often ends in ALI and ARDS.[12] Injury of alveolar epithelial cells impairs the permeability of the barrier between alveolar space and blood vessels. Epithelial cells release various chemokines such as IL-8, attracting more neutrophils in alveolar space. Stimulating factors present in alveolar space promote neutrophil activation and NETs release. Low levels of surfactant proteins such as SP-A and SP-B have been observed in many lung diseases. Douda et al., 2011; and Nayak et al., 2012, have found these proteins accountable for defective NET-nucleic acid clearance.[13],[14]

Saffarzadeh et al., 2012, reported that NE increases alveolar-capillary permeability by cleaving vascular endothelial-cadherin and E-cadherin. NE also induces apoptosis of epithelial cells, releasing pro-inflammatory cytokines.[15] The antibacterial and pro-inflammatory role of NETs was observed in cystic fibrosis (CF) patients. Cystic fibrosis patients produce a lot of mucus that is an excellent environment for bacteria development and can lead to chronic infection. Pathogens stimulate neutrophils to release neutrophil extracellular traps; an ineffective neutrophil extracellular traps clearance causes epithelium injury by neutrophil extracellular traps components, and increases mucus viscosity owing to the presence of DNA fibers.[1]


  Role of Neutrophil Extracellular Traps in Novel Coronavirus Disease-19 Top


NETs have also been detected in the lungs where they are involved in chronic inflammation processes in ALI/ARDS patients. Besides, DNA-protein complexes have been found in the airway fluids of CF patients, which may increase the viscosity of the sputum and negatively impact lung functions. Hence, their involvement in nCOVID-2019 can also be speculated. nCOVID-19 is a virus-induced respiratory disease that progresses to ARDS triggered by a cytokine storm. Respiratory failure from ARDS is the leading cause of nCOVID-19-associated mortality. The evidence suggests that a subgroup of patients with severe nCOVID-19 might have a cytokine storm syndrome. In a recent retrospective, multicentre study of 150 confirmed nCOVID-19 cases in Wuhan, China, elevated ferritin and IL-6 were found as predictors of fatality, suggesting that mortality might be due to virally driven hyperinflammation. The massive overproduction of cytokines by the host immune system (a phenomenon known as a “cytokine storm”) was formerly observed and investigated during the global outburst of SARS-CoV infection in 2003. During a cytokine storm, an excessive immune response damages healthy lung tissue, leading to acute respiratory distress and multiorgan failure in adverse cases. Beyond inflammation, mechanisms including endothelial activation, respiratory epithelial dysfunction, and surfactant depletion are established major contributors to ARDS pathogenesis.[10]

It has been discovered that the activation of endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) and cytosolic sensors by viral nucleic acids induces the production of IFNs and pro-inflammatory cytokines.[10]

Severe novel COVID-19 is associated with a cytokine storm characterized by increased plasma concentrations of IL-1β, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, IFN-γ, IFNγ-inducible protein 10, monocyte chemoattractant protein 1, granulocyte-colony stimulating factor, macrophage inflammatory protein 1α, and tumor necrosis factor-alpha (Huang et al., 2020; Mehta et al., 2020; Ruan et al., 2020; Wu et al., 2020; Wu and Yang, 2020; Zhang et al., 2020).[16],[17],[18],[19],[20],[21] In one study by Barnes et al. 2020, it was proposed that the exacerbated host response in patients with severe nCOVID-19 revolves around the aberrant hyperactivation of neutrophils.[22] This neutrophilia is responsible for cytokine storm, and it also predicts poor outcomes with nCOVID-19.[23] Barnes et al. examined lung autopsy samples of three nCOVID-19 patients at Weil Cornell Medicine and observed the neutrophil infiltration in pulmonary capillaries,[22] acute capillaries with fibrin deposition, extravasation of neutrophils into the alveolar space, and neutrophilic mucositis.[22] On autopsy lung examination of a 64-year-old male of Hispanic decent, it was found that the entire airway was affected and diseases such as diabetes, hemodialysis, end-stage kidney disease, heart failure, and hepatitis C can originate from ledipasvir/sofosbuvir therapy. They found no shreds of evidence of sepsis in this patient clinically, premortem cultures were negative, and the autopsy was performed within 5 h of death. Similar neutrophil distribution, but with less extensive infiltration, was observed in the two additional autopsies analyzed to date. These other two cases had a longer duration of symptoms.

Fox et al., 2020, and Yao et al., 2020, also noticed neutrophil infiltration in their respective studies on autopsied samples from COVID patients.[24],[25] All these findings of neutrophilia led us to speculate that it could be a source of excess NETs. NETs have been found in infection-related ALI models of influenza virus, bacteria or bacterial component LPS, and fungi. Substantial inflammation in the alveolar and plasma compartments has been a recognized characteristic of ARDS patients since the 1980s.[26]

NETs can also induce macrophages to secrete IL-1β and that IL-1β enhances NET formation in various diseases, including aortic aneurysms and atherosclerosis.[22] This suggests a circulating loop between macrophages and NETs, leading to uncontrollable, progressive inflammation. This loop can be seen in severe asthma.[27] According to Barnes et al., if a NET-IL-1β loop is activated in severe nCOVID-19, the uncontrolled production of NETs and IL-1β[22] could accelerate respiratory decompensation, the formation of microthrombi, and aberrant immune responses. Furthermore, IL-1β induces IL-6,[28] and IL-6 has emerged as a promising target for nCOVID-19 treatment.[17],[29] IL 6 can signal in two ways: classic and trans signaling (Calabrese and Rose-John, 2014). Trans-signaling is associated with pro-inflammatory states, and lower levels of soluble IL-6Rα are associated with better lung function in asthma.[22] Neutrophils can shed soluble IL-6R alpha in response to IL-8 (Marin et al., 2012), which is abundant in nCOVID-19 associated cytokine storm.[22]

Zuo et al. were the first ones to report about the elevated levels of serum NETs in many hospitalized patients with nCOVID-19 (n = 50 patients, n = 84 samples).[30] They measured three markers commonly used to detect NET remnants in the blood, which were cell-free DNA, MPO-DNA, and Cit-H3, and found significant elevations in all the three parameters. They have also found that nCOVID-19 sera are potent stimulators of NETosis when added to control neutrophils in vitro. Their data revealed high levels of NETs in many patients having nCOVID-19, where they may contribute to cytokine release and respiratory failure.[30]

Most of the clinical features of severe nCOVID-19, such as increased lung inflammation, thick mucus secretions, elevated serum cytokine levels, lung damage, and micro thrombosis, are similar to those seen in patients with diseases such as ARDS, severe coronary artery disease, and CF. Moreover, a variety of drugs that lead to the inhibition of NETs have been used in treating conditions related to it, supporting the theory that NETs may contribute to the clinical characteristics of nCOVID-19.


  Conclusion Top


There is much evidence that suggests an association between NETs and the cytokine storms seen in severe cases of nCOVID-19. Therefore, it can be postulated that nCOVID-19 induces a disproportionate virus-induced NET release, which can play a crucial role in nCOVID-19 pathogenesis. It is necessary to identify and treat hyper inflammation using existing, approved therapies with known safety profiles to immediately control and reduce the rising nCOVID-19 mortality.[17] The use of several specific anti-cytokine approaches to treat a variety of cytokine storm syndromes, including those triggered by viruses, has proven effective. These include drugs targeting IL-1, IL-6, IL-18, and IFN-gamma. Nevertheless, other scientists remain unsure if NETs remain necessarily dangerous or whether they may be useful in treating such types of the pandemic. Future studies should investigate the predictive accuracy of circulating NETs in longitudinal correlations, and determine whether NETs may be novel therapeutic targets in diseases like a severe nCOVID-19 pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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