Neutrophil extracellular traps in immunity and disease

Key Points

  • Neutrophil extracellular traps (NETs) protect against infection, in particular by large pathogens, but they are also implicated in the pathology associated with a growing number of immune-mediated conditions.

  • NET formation is triggered by innate immune receptors through downstream intracellular mediators that include reactive oxygen species (ROS), produced by NADPH oxidase or mitochondria, which activate myeloperoxidase (MPO), neutrophil elastase (NE) and protein-arginine deiminase type 4 (PAD4) to promote chromatin decondensation.

  • NETosis is induced in response to microbial cues and endogenous danger signals and must be tightly regulated to prevent excessive tissue damage during acute inflammation or chronic inflammatory and autoimmune disease. Microorganism size, microbial virulence factors and cytokines are regulators of NETosis.

  • NETs have several immune-modulatory functions that have been implicated in disease. They can prime other immune cells to induce sterile inflammation or potentiate autoimmunity by stimulating interferon responses owing to NET-associated oxidized DNA and antimicrobial peptides.

  • NETs can also occlude the vasculature by promoting thrombosis and obstruct important organ areas, capture metastatic tumours and delay wound healing in diabetes.

Abstract

Neutrophils are innate immune phagocytes that have a central role in immune defence. Our understanding of the role of neutrophils in pathogen clearance, immune regulation and disease pathology has advanced dramatically in recent years. Web-like chromatin structures known as neutrophil extracellular traps (NETs) have been at the forefront of this renewed interest in neutrophil biology. The identification of molecules that modulate the release of NETs has helped to refine our view of the role of NETs in immune protection, inflammatory and autoimmune diseases and cancer. Here, I discuss the key findings and concepts that have thus far shaped the field of NET biology.

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Figure 1: NET formation pathways.
Figure 2: Molecular mechanisms regulating NETosis.
Figure 3: NET evasion mechanisms.
Figure 4: Mechanisms of NET-mediated pathology.

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Acknowledgements

V.P. is supported by the Francis Crick Institute, which receives its core funding from the UK Medical Research Council, Cancer Research UK and the Wellcome Trust (FC001129).

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Glossary

Neutrophil elastase

(NE). A neutrophil-specific antimicrobial serine protease stored in azurophilic granules.

Myeloperoxidase

(MPO). A haem-containing enzyme that reacts with hydrogen peroxide to generate hypochlorite and other halide oxidants.

NADPH oxidase

A membrane-associated complex of proteins that transfer electrons from NADPH to molecular oxygen to generate the oxygen radical superoxide.

Azurophilic granules

A subset of neutrophil granules that contain antimicrobials such as myeloperoxidase and neutrophil elastase. Within the granule membranes, a complex of eight antimicrobial proteins forms the azurosome.

Chronic granulomatous disease

(CGD). An inherited X-linked immune deficiency caused by genetic mutations that disrupt the activity of NADPH oxidase. It is associated with hyperinflammation and increased susceptibility to bacterial and fungal infections.

Thrombosis

Formation of a blood clot (thrombus) in blood vessels, resulting in partial or complete vessel occlusion.

DEK

A DNA-binding protein that alters DNA structures and is involved in DNA repair.

Autophagy

An evolutionarily conserved process, in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation and recycling, through fusion with lysosomes.

Necroptosis

A form of programmed necrosis that is initiated by the kinases receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 in response to external signals, in conditions in which caspase 8 activity is compromised.

Damage-associated molecular patterns

(DAMPs). Conserved mammalian motifs, recognized by pattern recognition receptors, that are broadly upregulated in response to cellular stress and that trigger an innate immune response. Examples include heat shock proteins, high mobility group protein B1 (HMGB1), DNA-binding proteins and uric acid.

Cystic fibrosis

An autosomal recessive genetic condition secondary to mutations in the cystic fibrosis transmembrane conductance regulator (a chloride channel), causing lung, gastrointestinal, endocrine and fertility complications. Chronic infection of the lungs is associated with sputum that is rich in neutrophil proteins and DNA.

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Papayannopoulos, V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol 18, 134–147 (2018). https://doi.org/10.1038/nri.2017.105

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