Infographic: How NETs Work
Infographic: How NETs Work
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Infographic: How NETs Work

While neutrophil extracellular traps help guard the body from infection, they also can contribute to a range of diseases.

Borko Amulic and Gabriel Sollberger
Oct 1, 2019

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When a neutrophil encounters a pathogen, it can respond in several ways: phagocytosis, degranulation, or by releasing neutrophil extracellular traps (NETs). In NET release, shown here, the enzyme complex NADPH oxidase generates reactive oxide species (ROS), which in turn initiate the disintegration of granules, releasing neutrophil elastase (NE). NE then migrates to the neutrophil’s nucleus, where it cleaves proteins that package the cell’s DNA as chromosomes. The chromatin expands until it fills up the entire cell, which breaks open and extrudes the NET into the extracellular space. There, the webs are thought to trap and kill the triggering pathogens. 

NET Formation

When a neutrophil encounters a pathogen, it can respond in several ways: phagocytosis, degranulation, or by releasing neutrophil extracellular traps (NETs). In NET release, shown here, the enzyme complex NADPH oxidase generates reactive oxide species (ROS), which in turn initiate the disintegration of granules, releasing neutrophil elastase (NE). NE then migrates to the neutrophil’s nucleus, where it cleaves proteins that package the cell’s DNA as chromosomes. The chromatin expands until it fills up the entire cell, which breaks open and extrudes the NET into the extracellular space. There, the webs are thought to trap and kill the triggering pathogens. 

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NETS IN HEALTH

The exact contribution of NETs to antimicrobial defense has been difficult to nail down, but researchers are slowly elucidating their roles in protecting the body from invaders and other threats, including runaway inflammation. Those roles include:

Trapping

NETs immobilize microbes and prevent their dissemination.


Barriers

NETs can form dense, exclusionary barriers in the eye that prevent microbes from penetrating the body.


Immune signaling

NET components act as alarm signals to activate additional immune cells and propagate the inflammatory response. Macrophages and dendritic cells sense various components of the NETs, including DNA and proteins, which leads them to produce proinflammatory mediators.


Countering inflammation

When present at high density, NETs can cleave proinflammatory cytokines and help resolve inflammation.


. . . AND DISEASE

NETs have a dark side that makes them dangerous when inappropriately deployed. The structures have been implicated as contributors to a range of conditions.

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1

Cancer

NET-associated proteins lead to reawakening of dormant cancer cells and convert them to proliferating metastatic cells.

2

Malaria

NET formation is triggered during malaria, and then the structures are cleaved into fragments by circulating DNase1. These fragments lead to upregulation of cytoadhesion receptors on the surface of endothelial cells lining the blood vessels. Cells infected with Plasmodium parasites bind to these receptors, which helps them avoid the immune response in the spleen and causes damaging inflammation.

3

Thrombosis

NET components promote blood coagulation and obstruction of small blood vessels.

4

Atherosclerosis

NETs activate macrophages, inducing them to produce proinflammatory cytokines. The histones associated with NETs also damage the smooth muscle of the arterial walls.

5

Lupus

This autoimmune disease is characterized by production of autoantibodies directed against one’s own DNA. NETs are thought to be a source of autoantigens, as well as immunostimulatory molecules that activate dendritic cells and fuel inflammation.

Read the full story.