Polymorphonuclear neutrophils (PMNs) are the most abundant leukocytes in the blood and are considered as the first line of innate immune defence against infectious diseases. However, PMN cells have a crucial function in both innate and adaptive immune responses. Neutrophils have several mechanisms to control pathogens, and one of them is their capability to form neutrophil extracellular traps (NETs) that may control infection. NETs have the capacity to trap microorganisms, kill them, or avoid their dissemination. The aim of this chapter is to provide a comprehensive review on NETs, the cells that produce them, and some of the mechanisms involved in their formation, their role in the immune response, and the pros and cons of NETs, focusing mainly on infectious diseases.
- neutrophil extracellular traps (NETs)
- infectious diseases
The polymorphonuclear neutrophils (PMNs), first reported by IIya IIych Mechnikov, better known as Élie Metchnikoff, are the most abundant leukocytes (60%) in the blood. These PMNs are considered as the first line of innate immune response against infectious agents . Later on, Carl Friedrich Claus suggested the term of phagocytosis for the function of these cells. Studies aimed at the fully understanding of their properties and functions in controlling a variety of pathogens are still in progress. Research on neutrophils has focused on their phagocytic capacity and, more recently, on their role as neutrophil extracellular traps (NETs) forming cells, in innate and adaptive immunity.
When neutrophils fail to kill invading pathogens by the classical phagocytosis mechanism, PMNs can accomplish this function by neutrophil extracellular traps (NETs), a process reported as a novel form of cell death called NETosis, which is dependent of the generation of reactive oxygen species [2–5]. Neutrophils forming NETs have been demonstrated by activating neutrophils with phorbol myristate acetate (PMA), interleukin 8 (IL-8), lipopolysaccharide (LPS), or under contact of neutrophils with Gram-negative and Gram-positive bacteria.
NETosis induction has also been described for viral infections, and some of the signaling pathways involved have been analyzed, finding the involvement of pathogen-associated molecular patterns (PAMPs), TLR-4, TLR-7, and TLR-8. Rodríguez-Espinosa et al. have shown that NETs formation takes place in two separate metabolic steps: the first one involves chromatin decondensation, which is independent of external glucose and glycolysis, whereas the second, which involves the chromatin release, is a process that is dependent on external glucose and glycolysis .
2. Understanding the process of NETs formation
The neutrophil extracellular traps (NETs) structures were described as another type of neutrophil cell death, different from apoptosis and necrosis. The research field on NETs has steadily been growing since 2004, when Brinkmann et al. reported for the first time this new function of activated neutrophils, demonstrating, by electron microscopy, that, when neutrophils are in the presence of bacteria, fungi, protozoa, or viruses, they acquire the capacity to form fibrillary structures, resembling nets or webs. These structures are composed mainly of nuclear material, chromatin fibers with diameters of 15–17 nm containing DNA decorated with neutrophil elastase (NE), myeloperoxidase (MPO), cathepsin G, proteinase 3 (PR3), high-mobility group protein B1 (HMGB-1), tryptase or antimicrobial peptide LL37, histones, and cytoplasmic proteins such as histones H1, H2A, H2B, H3, H4, G, lactoferrin, and gelatinase, among others .
Two mechanisms for the formation of NETs have been described: the suicide or lytic and vital NETosis . In the first case, NETs release results from the activation of PMN by IL-8 or chemical compounds, such as phorbol myristate acetate (PMA). PMA activates neutrophils through the protein kinase C (PKC) and follows the Raf-MEK-ERK mitogen-activated protein kinase signaling pathway; the enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase induces the translocation of elastase from the cytosolic granules to the inner nucleus, helping the rupture of the chromatin through histones. Induction of NETs with PMA by this mechanism can be observed from 30 min post-activation and, by 6–8 h post-activation, a high number of extracellular traps (ETs) are well formed (Figure 1).
In contrast, vital NETosis has been demonstrated following pathogen recognition by host pattern recognition receptors (PRRs). Gram-negative bacteria products, such as lipopolysaccharide (LPS), activate neutrophils, by the ligation of TLRs (TLR-4 in the case of LPS), inducing the liberation of NETs. In the case of Gram-positive bacteria, the complement receptor 3 (CR3) and TLR-2 are required to induce vital NETosis; platelets are also inducers of vital NETosis, through CD11a. This mechanism maintains the external membrane integrity and thus the function of neutrophils, until cells are devoid of nucleus [7, 8].
A third mechanism for the induction of NETs, recently reported, is through autophagy [9, 10]. It is worth mentioning that neutrophils are not the only cells that form extracellular traps (ETs), and other immune cells, such as mast cells, eosinophils, and macrophages, can also release ETs. Although the molecular principles underlying the formation of ETs by mast cells , eosinophils , and monocytes/macrophages  are similar to those observed in neutrophils, there are some notable disparities. The most remarkable mechanism of ET formation has been described in eosinophils. In these cells, ETs are formed by both nuclear and mitochondrial DNAs, in a reactive oxygen species (ROS)-dependent manner.
Neutrophil extracellular traps are able to capture microorganisms trap microorganisms, killing them or not, this much depends on the type of pathogen involved. NETs are produced by the neutrophils of mice, humans, and some other animals, and can be induced by chemical compounds, bacteria, fungi, protozoa, and viruses. The role of NETs in viral infections is not yet clear. However, some viruses induce the release of NETs [14, 15].
While some viruses are immobilized and inactivated by NETs, others such as HIV induce the production of an IL-10-like protein that inhibits the formation of NETs , and dengue virus inhibits PMA-induced formation of NETs. Interestingly, neutrophils seem to be arrested at the chromatin decondensation step, failing to liberate NETs, thus suggesting a metabolic-related mechanism of NETs inhibition .
Controversy surrounding neutrophil extracellular traps as a host defense mechanism makes it necessary to analyze how NETs limit the growth of various infectious agents, whereas, apparently, they have no effect on others. On the other hand, how NETs may cause damage and autoimmune diseases also needs to be investigated.
3. Neutrophil extracellular traps in bacterial infections
Several mechanisms have been proposed to explain how NETs control bacterial infection. NETs bind to both Gram-negative and Gram-positive bacteria, precluding bacterial mobilization and dissemination, and some bacteria are killed extracellularly by NETs, due to their high content of serine proteases . Some bacteria and their interaction with NETs are summarized as follows:
In summary, this review shows that in response to bacterial stimuli, neutrophils get activated and form NETs that may trap and kill invading bacteria. Besides the “classical” way of clearing pathogens by phagocytosis and intracellular exposure to bactericidal compounds, this novel mechanism of neutrophil extracellular killing plays an important role in primary host defense. Moreover, knowledge on the mechanisms of bacterial adaptation to evade the immune system could be used in the medical practice. For instance, DNases inhibitors can be used as potential therapeutics, to prevent degradation of NETs by Group A Streptococcus DNases. In the future, therapeutics aimed at the maintenance of NETs could be used to help clear bacterial infections.
4. Neutrophil extracellular traps in parasitic infections
Neutrophil extracellular traps have been broadly studied in regard to bacteria. The role of NETs against protozoa, however, has just recently been analyzed. Protozoa can induce NETs in neutrophils and macrophages, and knowledge on the mechanisms at play is just emerging.
In 2011, Abdi Abdallah  reported that human neutrophils produce NETs in response to stimulation with
Leishmania spp. These protozoal parasites are the causative agents of leishmaniosis, and the leishmaniosis model has been quite useful in studies on the role of NETs at the early stages of the disease. The promastigote has been identified as the main parasite stage as inducer of NETs. Promastigotes and amastigotes numbers diminish upon NETs release. Histones H2A and H2B are the main inducers of NETs, and these are highly toxic for the parasite. The promastigote form of the parasite can evade the NETs by means of its 3′ nucleotidase, enzyme that degrades the DNA, allowing
In 2015, Rochael et al. analyzed the role of reactive oxygen species, neutrophil elastase, myeloperoxidase, and the PAD4 enzyme in the formation of NETs by
As previously described, the interaction of
Ávila et al. demonstrated that parasite growth could only take place in the absence of a calcium chelant, since enzymes such as trophozoite DNAsas require calcium. This provides an example of NETs inhibition by parasite-produced enzymes.
5. Neutrophil extracellular traps in fungus infection
Aspergillus fumigatus and Aspergillus nidulans
Recent reports highlight the importance of glucosaminoglycans (GAG) in
Fungus resistance to neutrophil-mediated killing positively correlates with the amount of cell wall-associated GAG. Fungus GAG content functions as the analog of bacterial capside, enhancing resistance to NETs. Although the mechanism by which exopolysaccharides mediate resistance to NETs has not been defined, it is suggested that GAG may inhibit hyphae-NETs binding, perhaps due to the repulsion between the
5.2. Candida albicans
In 2006, Urban et al. showed that NETs can kill
Experiments aimed at analyzing the effect that PMA-activated NETs have on
The analysis of the components present in the neutrophil granules that may be responsible for the killing of
Kenno et al. analyzed the induction of NETs by
5.3. Cryptococcus neoformans
In 2015, Rocha et al. described that the opportunistic fungus
The release of NETs by the acapsular strain of
6. Neutrophil extracellular traps in viral infections
Viruses have an extraordinary ability to evade the immune system, and the innate immune system is regarded as the first line of defense. Innate immune cells recognize a wide variety of pathogens through their pattern-recognition receptors (PRRs) that include Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-like receptors (RLRs) that recognize pathogen-associated molecular patterns (PAMPs). Several PRRs recognize viral ligands such as TLR-3, TLR-7, TLR-8, RIG-1, and MDA5, and the activation of these PRRs induces the synthesis of antiviral interferons (types I and II), tumor necrosis factor α, interleukin-15, and interleukin-18 [53–55].
The role of NETs in the control of several bacterial infections has been broadly analyzed. However, research on their role in viral infections remains scarce. It has recently been shown that viral infections or virus-derived molecules may act as strong inducers of NETs. Several viruses that induce the formation of NETs have been identified. In some cases, NETs neutralize the viral particles by the MPO or the granule-derived defensins, associated to NETs. The α-defensin protein directly inhibits the influenza virus replication and protein synthesis . Some viruses, such as those of the herpesvirus family, contain proteins with endonuclease activity, so they can degrade NETs and allow viral escape and dissemination. NETs anti-viral activity consists in the sequestering of viral particles, thus preventing fusion of viruses with target cells and direct neutralization of virions. It is worth mentioning that viruses do not necessarily infect the neutrophils. However, neutrophils can sense viral particles through their PRRs or via secondary signals produced upon infection of other host cells. The use of secondary signals to induce the release of NETs has important advantages in the context of viral infections [56, 57].
Viruses that induce the release of NETs
In 2015, Moreno-Altamirano et al.  demonstrated that dengue virus serotype-2 inhibits PMA-induced formation of NETs, arresting neutrophils at the chromatin de-condensation step which, based on a previous report , suggests that DENV-2 inhibits the formation of NETs by interfering with glucose uptake and glycolysis.
Anti-microbial properties of NETs have been shown for bacteria, protozoa, fungus, and virus. Understanding how neutrophil extracellular traps (NETs) limit the growth of some infectious agents, whereas, apparently, they have no effect on others, and how NETs may cause tissue damage and contribute to the development of pathologies, such as autoimmune diseases, will help to exploit their anti-pathogen properties at full, and to limit their pathogenic effects, in clinical settings. It is quite likely that this research field will continue providing exciting findings.
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