Neutrophil extracellular traps

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A scanning electron microscope image of NETs engulfing fungal cells (Candida albicans) in an infected mouse lung. (Click on image for more details.)[1]
Fluorescent image of cultivated neutrophils isolated from venous blood of human with Alzheimer Disease. Sample was treated with Hoechst 33342 dye that is used to stain DNA. The picture shows the release of DNA by a neutrophil as foggy area in the center of the view field indicating the spontaneous activation of neutrophil extracellular traps (NETs) formation in AD patients that is not usually observed in healthy mates. Magnification x40.

Neutrophil extracellular traps (NETs) are networks of

proteins and chromatin to form an extracellular fibril matrix known as NET through an active process.[2]

Structure and composition

High-resolution scanning

electron microscopy has shown that NETs consist of stretches of DNA and globular protein domains with diameters of 15–17 nm and 25 nm, respectively. These aggregate into larger threads with a diameter of 50 nm.[2] However, under flow conditions, NETs can form much larger structures, reaching hundreds of nanometers in length and width.[4]

Analysis by immunofluorescence corroborated that NETs contain proteins from azurophilic granules (neutrophil elastase, cathepsin G and myeloperoxidase), specific granules (lactoferrin), tertiary granules (gelatinase), and the cytoplasm; however, CD63, actin, tubulin and various other cytoplasmatic proteins are not present in NETs.[2][5]

Anti-microbial activity

NETs disarm pathogens with antimicrobial proteins such as

proteases from diffusing away and inducing damage in tissue adjacent to the site of inflammation. NET formation has also been shown to augment macrophage bactericidal activity in response to multiple bacterial pathogens.[7][8]

More recently, it has also been shown that not only bacteria but also pathogenic

fungi such as Candida albicans induce neutrophils to form NETs that capture and kill C. albicans hyphal as well as yeast-form cells.[9] NETs have also been documented in association with Plasmodium falciparum infections in children.[10]

While it was originally proposed that NETs would be formed in tissues at a site of bacterial/yeast infection, NETs have also been shown to form within

TLR4 and then bind to and activate neutrophils to form NETs. Platelet-induced NET formation occurs very rapidly (in minutes) and may or may not result in death of the neutrophils.[11] NETs formed in blood vessels can catch circulating bacteria as they pass through the vessels. Trapping of bacteria under flow has been imaged directly in flow chambers in vitro and intravital microscopy demonstrated that bacterial trapping occurs in the liver sinusoids and lung capillaries (sites where platelets bind neutrophils).[4]

NETosis

NET activation and release, or NETosis, is a dynamic process that can come in two forms, suicidal and vital NETosis. Overall, many of the key components of the process are similar for both types of NETosis, however, there are key differences in stimuli, timing, and ultimate result.[12]

Activation pathway

The full NETosis activation pathway is still under investigation but a few key proteins have been identified and slowly a full picture of the pathway is emerging. The process is thought to begin with

PAD4) via reactive oxygen species (ROS) intermediaries. PAD4 is responsible for the citrullination of histones in the neutrophil, resulting in decondensation of chromatin.[12] A NADPH oxidase–independent form of NETosis, relying solely on mitochondrial-derived ROS, has been also been described.[13] Azurophilic granule proteins such as myeloperoxidase (MPO) and neutrophil elastase (NE) then enter the nucleus and further the decondensation process, resulting in the rupture of the nuclear envelope. The uncondensed chromatin enters the cytoplasm where additional granule and cytoplasmic proteins are added to the early-stage NET. The result of the process then depends on which NETosis pathway is activated.[12]

Suicidal NETosis

Suicidal NETosis was first described in a 2007 study that noted that the release of NETs resulted in neutrophil death through a different pathway than

antibodies, PMA, and so on.[12][15] The current understanding is that upon activation of these receptors, downstream signaling results in the release of calcium from the endoplasmic reticulum. This intracellular influx of calcium in turn activates NADPH oxidase, resulting in activation of the NETosis pathway as described above.[15] Of note, suicidal NETosis can take hours, even with high levels of PMA stimulation, while vital NETosis can be completed in a matter of minutes.[12]

Vital NETosis

Vital NETosis can be stimulated by bacterial lipopolysaccharide (LPS), other "bacterial products, TLR4-activated platelets, or complement proteins in tandem with

blebbing of the nucleus, resulting in a DNA-filled vesicle that is exocytosed and leaves the plasma membrane intact.[12] Its rapid formation and release does not result in neutrophil death. It has been noted that neutrophils can continue to phagocytose and kill microbes after vital NETosis, highlighting the neutrophil's anti-microbial versatility.[15]

Regulation

The formation of NETs is regulated by the

macrophages that phagocytose and degrade them.[17]

NET-associated host damage

NETs might also have a deleterious effect on the host, because the extracellular exposure of histone complexes could play a role during the development of

preeclampsia, a pregnancy-related inflammatory disorder in which neutrophils are known to be activated.[19] NETs have also been reported in the colon mucosa of patients with the inflammatory bowel disease ulcerative colitis.[20] NETs have also been associated with the production of IgG antinuclear double stranded DNA antibodies in children infected with P. falciparum malaria.[10]

NETs have also been found in cancer patients.[21] Significantly higher levels of NETs have been detected in cancer patients compared to healthy controls, and have been associated with poor prognosis and clinical outcome.[22] Preclinical research suggests that NETs are jointly responsible for cancer-related pathologies like thrombosis, organ failure and metastasis formation.[23] NETs can cause peripheral organ failure or organ dysfunction in cancer patients by obstructing vasculature, causing an inflammatory response, and by releasing cytotoxic components with a direct damaging effect on the tissue.[24]

NETs have been shown to contribute to the pathogenesis of HIV/SIV. NETs are capable of capturing HIV virions and destroying them.[25] There is an increase in NET production throughout the course of HIV/SIV, which is reduced by ART. In addition, NETs are able to capture and kill various immune cell groups such as CD4+ and CD8+ T cells, B cells, and monocytes. This effect is seen not only with neutrophils in the blood, but also in various tissues such as the gut, lung, liver, and blood vessels. NETs possibly contribute to the hypercoagulable state in HIV by trapping platelets, and expressing tissue factor.[26]

NETs also have a role in thrombosis and have been associated with stroke.[27][28][29]

These observations suggest that NETs might play an important role in the pathogenesis of infectious, inflammatory and thrombotic disorders.[30][31][32]

Due to the charged and 'sticky' nature of NETs, they may become a problem in cystic fibrosis sufferers, by increasing sputum viscosity. Treatments have focused on breaking down DNA within sputum, which is largely composed of host NET DNA.

A small study published in the journal

ST-elevation myocardial infarctions.[33]

References

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External links
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