Neutrophil extracellular traps: casting the NET over pathogenesis
Introduction
Polymorphonuclear leukocytes (neutrophils) are important players in the first line of defense against invading microbial pathogens. Their role in phagocytic uptake and intracellular killing of pathogens has been well described previously [1, 2]. In 2004 neutrophils were shown to form neutrophil extracellular traps (NETs) that bind, disarm and kill pathogens extracellularly [3]. Five aspects of NETs are covered below: NET structure; NET induction and formation; the role of NETs in disease; escaping from NETs; and other extracellular means for bacterial trapping.
Section snippets
NET structure
NETs are assembled from granular and nuclear constituents of neutrophils (see Figure 1a). The granule components are peptides and enzymes (e.g. elastase and myeloperoxidase) that are normally stored in distinctive neutrophil granules. The nuclear constituents are chromatin DNA and histones. DNA is the major structural component of NETs and it provides the backbone on which the proteinaceous effectors reside. Hence, treatment with DNase results in disintegration of the NETs. Membranes, membrane
NET induction and formation
Brinkmann et al. [3] showed that NETs are made by neutrophils activated with interleukin-8 (IL-8), phorbol myristate acetate (PMA) or lipopolysaccharide, but not by naïve cells. However, not much is known about exact induction pathways (for an overview of known stimuli leading to NET formation, see Figure 1b). Martinelli et al. [4] found, using a microarray approach, that mature neutrophils, in contrast to immature neutrophils, strongly express interferon target genes. Their functional in vitro
Role of NETs in disease
NETs interact with a variety of different pathogens. They capture both Gram-positive (Staphylococcus aureus, Streptococcus pneumoniae and Group A streptococci [GAS]) and Gram-negative bacteria (Salmonella enterica serovar Typhimurium and Shigella flexneri) as well as fungi (Candida albicans). By providing a high local concentration of antimicrobial proteins, NETs could disarm and kill bacteria, as has been shown for S. aureus, GAS and S. flexneri [3, 6•]. Antimicrobial proteins include
Other extracellular means for bacterial trapping
Confinement of an infection to a local site in the body might be an important function of NETs. However, NETs are not the only means of entrapment. In insects, an innate immune mechanism named hemolymph coagulation has been described. The hemolymph coagulation is important for sealing wounds, trapping microbes and for blocking their entry [18]. Despite striking similarities between the clots formed in insects and mammalian neutrophil NETs, clots formed in Drosophila do not contain any
Conclusion
Neutrophils are an important host defense against invading pathogens. It has, however, been an enigma as to how neutrophils mediate defense against encapsulated bacteria such as pneumococci, that in the absence of opsonization are not readily phagocytosed. NETs represent a novel mechanism by which neutrophils contribute to host defense. These traps are composed of DNA, histones and other antibacterial components, with the potential to confine, as well as kill bacteria and fungi. Recent data
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
We thank Arturo Zychlinsky for critically reading the manuscript and for his helpful comments. This work was supported by Marie Curie Early Stage Research Training Fellowships of the European Community's 6th Framework Programme (called IMO-train and EIMID), the EU programme PREVIS in 6th Framework Programme, Torsten and Ragnar Söderbergs foundation, Swedish Royal Academy of Sciences and the Swedish Research Council.
References (23)
- et al.
How do neutrophils and pathogens interact?
Curr Opin Microbiol
(2004) - et al.
Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation
J Biol Chem
(2004) - et al.
DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps
Curr Biol
(2006) - et al.
Methylation of histones in myeloid leukemias as a potential marker of granulocyte abnormalities
J Leukoc Biol
(2005) - Wartha F, Beiter K, Albiger B, Fernebro J, Zychlinsky A, Normark S, Henriques-Normark B: Capsule and D-alanylated...
- et al.
Immunology. The tangled webs that neutrophils weave
Science
(2004) - et al.
Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response
Proc Natl Acad Sci USA
(2005) - et al.
Pulmonary surfactant proteins A and D enhance neutrophil uptake of bacteria
Am J Physiol
(1998) - et al.
Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity
Blood
(2005) Neutrophils and immunity: challenges and opportunities
Nat Rev Immunol
(2006)
Neutrophil extracellular traps kill bacteria
Science
Cited by (173)
High yield expression in Pichia pastoris of human neutrophil elastase fused to cytochrome B5
2023, Protein Expression and PurificationPhthalide derivative CD21 regulates the platelet- neutrophil extracellular trap-thrombin axis and protects against ischemic brain injury in rodents
2023, International ImmunopharmacologyProtective effects of chicoric acid on LPS-induced endometritis in mice via inhibiting ferroptosis by Nrf2/HO-1 signal axis
2022, International ImmunopharmacologyAutophagy-driven NETosis is a double-edged sword – Review
2020, Biomedicine and Pharmacotherapy