Neutrophil extracellular traps: casting the NET over pathogenesis

doi:10.1016/j.mib.2006.12.005

Current Opinion in Microbiology

Volume 10, Issue 1, February 2007, Pages 52-56

https://doi.org/10.1016/j.mib.2006.12.005 Get rights and content

Neutrophil extracellular traps (NETs) are considered to be part of the human innate immunity because they trap and kill pathogens. NETs are formed by activated neutrophils and consist of a DNA backbone with embedded antimicrobial peptides and enzymes. They are involved in host defense during pneumococcal pneumonia, streptococcal necrotizing fasciitis, appendicitis and insemination. Recently, bacterial virulence factors that counteract NETs have been identified. These include the degradation of the NET-backbone by DNases enabling the liberation of bacteria from NETs, as well as capsule formation, which reduces bacterial trapping. Furthermore, pathogens can resist NET-mediated killing by adding positive charge to their cell surface.

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.

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Autophagy is a cellular mechanism responsible for delivering protein aggregates or damaged organelles to lysosomes for degradation. It is also simultaneously a precise regulatory process, which is crucial for dealing with hunger, oxidative stress, and pathogen defense. Neutrophil Extracellular Traps (NETs), which form a part of a newly described bactericidal process, are reticular structures composed of a DNA backbone and multiple functional proteins, formed via a process known as NETosis. NETs exert their anti-infection activity by capturing pathogenic microorganisms, inhibiting their spread and inactivating virulence factors. However, NETs may also activate an immune response in non-infectious diseases, leading to tissue damage. Although the mechanism underlying this phenomenon is unclear, a large number of studies have suggested that autophagy may be involved. Autophagy-mediated NETs not only induce inflammation and tissue damage, but can also lead to cell senescence, malignant transformation, and cell death. Autophagy-dependent NETs also play a beneficial role in the hostwith respect to pathogen clearance and immune defense. Through careful review of the literature, we have found that the distinct roles of autophagy in NETosis may be dependent on the extent of autophagy and the specific manner in which it was induced. This article summarizes numerous recent studies, and reviews the role of autophagy-driven NETosis in various diseases, in the hope that this will lead to the development of more effective treatments.

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Current Opinion in Microbiology

Introduction

Section snippets

NET structure

NET induction and formation

Role of NETs in disease

Other extracellular means for bacterial trapping

Conclusion

References and recommended reading

Acknowledgement

References (23)

How do neutrophils and pathogens interact?

Curr Opin Microbiol

Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation

J Biol Chem

DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps

Curr Biol

Methylation of histones in myeloid leukemias as a potential marker of granulocyte abnormalities

J Leukoc Biol

Immunology. The tangled webs that neutrophils weave

Science

Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response

Proc Natl Acad Sci USA

Pulmonary surfactant proteins A and D enhance neutrophil uptake of bacteria

Am J Physiol

Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity

Blood

Neutrophils and immunity: challenges and opportunities

Nat Rev Immunol

Neutrophil extracellular traps kill bacteria

Science

Cited by (173)

Revealing the diversity of endogenous peptides and parent proteins in human colostrum and mature milk through peptidomics analysis

High yield expression in Pichia pastoris of human neutrophil elastase fused to cytochrome B5

Phthalide derivative CD21 regulates the platelet- neutrophil extracellular trap-thrombin axis and protects against ischemic brain injury in rodents

Protective effects of chicoric acid on LPS-induced endometritis in mice via inhibiting ferroptosis by Nrf2/HO-1 signal axis

Increased levels of NETosis in myeloproliferative neoplasms are not linked to thrombotic events

Autophagy-driven NETosis is a double-edged sword – Review