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Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system

Key Points

  • Neutrophil extracellular traps (NETs) are extracellular structures composed of chromatin coated with histones, proteases and granular and cytosolic proteins that help catch and kill microorganisms

  • Kupffer cells and neutrophils in the liver cooperate to eliminate pathogens in circulation

  • NETs have a potential role in gastrointestinal infection and sepsis, whereas several pathogenic bacteria are capable of escaping or hijacking NET-mediated capturing and killing

  • Excess NET formation is associated with the pathology of inflammatory liver and gastrointestinal diseases

  • Exposure to components of NETs might generate autoantibodies in gastrointestinal autoimmune diseases and facilitate the inappropriate immune response

  • Therapies that target key pathways in NET formation, with or without other treatments, might improve the treatment for gastrointestinal inflammatory diseases, cancer and thrombosis

Abstract

Neutrophil extracellular traps (NETs) have an important role during infection by helping neutrophils to capture and kill pathogens. However, evidence is accumulating that uncontrolled or excessive production of NETs is related to the exacerbation of inflammation and the development of autoimmunity, cancer metastasis and inappropriate thrombosis. In this Review, we focus on the role of NETs in the liver and gastrointestinal system, outlining their protective and pathological effects. The latest mechanistic insights in NET formation, interactions between microorganisms and NETs and the relationship between neutrophil subtypes and their functions are also discussed. Additionally, we describe the potential importance of NET-related molecules, including cell-free DNA and hypercitrullinated histones, as biomarkers and targets for therapeutic intervention in gastrointestinal diseases.

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Figure 1: Mechanisms of neutrophil extracellular trap formation.
Figure 2: Kupffer cells and neutrophils cooperate to capture bacteria in the liver vasculature.
Figure 3: Excessive neutrophil extracellular trap formation induced by inflammation causes tissue injury.
Figure 4: Tumour-induced neutrophil extracellular trap formation facilitates tumorigenesis and thrombus formation.

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Acknowledgements

The authors thank Servier for providing Servier Medical Art, which was used for creation of original figures. The work in the authors' laboratories is supported by grants from the Canadian Institutes of Health Research, Alberta Innovates Health Solutions, the Heart and Stroke Foundation of Canada and the Canada Research Chairs programme.

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M.H. contributed to all aspects of this manuscript. P.K. provided substantial contributions to the discussion of content and reviewed and edited the manuscript before submission.

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Correspondence to Paul Kubes.

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Glossary

Chromatin

A structure in the eukaryotic cell nucleus that contains primarily DNA and nuclear proteins such as histones.

Necrosis

Unprogrammed death of cells and living tissue induced by external or internal factors.

Neutrophil elastase

A serine protease secreted by neutrophils during inflammation.

Myeloperoxidase

The most abundant protein of neutrophils; catalyses the conversion of H2O2 and chloride into hypochlorous acid.

NADPH oxidase complex

A membrane-bound enzyme complex that produces reactive oxygen species when activated.

Hypercitrullination

The hyperactive conversion of arginine to citrulline.

Chemotax

The movement of organisms responding to chemical stimuli.

Phagocytose

The process by which phagocytes ingest or engulf other cells or particles.

Mitophagy

The specific process for the autophagic elimination of damaged mitochondria.

Transfection

The introduction of a segment of DNA or RNA into a eukaryotic cell by use of various physical or chemical methods or through viral infection.

Kupffer cells

Self-sustaining, liver-resident macrophages found in the liver sinusoids.

Liver sinusoids

Sinusoidal blood vessels that are lined with endothelial cells and that receive blood from terminal branches of the hepatic artery and portal vein and deliver it into central veins.

Complement receptor of immunoglobulin superfamily

A macrophage complement receptor that recognizes the activated form of complement C3, which opsonizes pathogens, apoptotic cells and foreign antigens.

von Willebrand factor

A large multimeric glycoprotein circulating in blood plasma that binds coagulation factor VIII and platelets and that mediates platelet adhesion to collagen at sites of vascular injury.

Damage-associated molecular patterns

Host biomolecules released by cellular injury that act as endogenous danger signals to activate the inflammatory response.

Cytokine storm

Uncontrolled excessive cytokine release that leads to detrimental effects, including leakage from capillaries, tissue oedema, organ failure and shock.

Anti-neutrophil cytoplasmic autoantibodies

Autoantibodies that bind to enzymes from neutrophil cytoplasmic granules and are biomarkers for a number of autoimmune diseases.

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Honda, M., Kubes, P. Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. Nat Rev Gastroenterol Hepatol 15, 206–221 (2018). https://doi.org/10.1038/nrgastro.2017.183

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