Neutrophil extracellular traps
Encyclopedia
Neutrophil extracellular traps (NETs) are networks of extracellular
fibers, primarily composed of DNA from neutrophils, which bind pathogens.
It has long been known that neutrophils (our front-line of defence against infection) use two strategies to kill invading pathogens: engulfment of microbes and secretion of anti-microbials. In 2004, a novel third function was identified: formation of NETs, whereby neutrophils kill extracellular pathogens while minimizing damage to the host cells. Upon in vitro
activation with the pharmacological agent phorbol myristate acetate
(PMA), Interleukin 8
(IL-8) or lipopolysaccharide
(LPS), neutrophils release granule proteins and chromatin
to form an extracellular fibril matrix known as NETs through an active process.
More recently, it has also been shown that not only bacteria but also pathogenic fungi such as Candida albicans
induces neutrophils to form NETs that capture and kill C. albicans hyphal as well as yeast-form cells. NETs have also been documented in association with Plasmodium falciparum infections in children. NETs disarm pathogens with antimicrobial proteins such as neutrophil elastase and histones that are bound to the DNA. NETs provide for a high local concentration of antimicrobial components and bind, disarm, and kill microbes extracellularly independent of phagocytic uptake. In addition to their antimicrobial properties, NETs may serve as a physical barrier that prevents further spread of the pathogens. Furthermore, delivering the granule proteins into NETs may keep potentially injurious proteins like proteases from diffusing away and inducing damage in tissue adjacent to the site of inflammation
. NETs might also have a deleterious effect on the host, because the exposure of extracellular histone complexes could play a role during the development of autoimmune diseases like lupus erythematosus
. NETs could also play a role in inflammatory diseases, as NETs could be identified in preeclampsia, a pregnancy related inflammatory disorder in which neutrophils are known to be activated. NETs also have been shown to be associated with the production of IgG antinuclear double stranded DNA antibodies in children infected with falciparum malaria.
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 . However, under flow conditions, NETs can form much larger structures, hundreds of nanometers in length and width.
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 blood vessel
s during sepsis
(specifically in the lung capillaries and liver sinusoid
s). Intra-vascular NET formation is tightly controlled and is regulated by platelet
s, which sense severe infection via platelet TLR4 and then bind to and activate neutrophils to form NETs. Platelet-induced NET formation occurs very rapidly (in minutes) and does not result in death of the neutrophils. 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)
These observations suggest that NETs might play an important role in the pathogenesis of infectious and inflammatory disorders.
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
fibers, primarily composed of DNA from neutrophils, which bind pathogens.
It has long been known that neutrophils (our front-line of defence against infection) use two strategies to kill invading pathogens: engulfment of microbes and secretion of anti-microbials. In 2004, a novel third function was identified: formation of NETs, whereby neutrophils kill extracellular pathogens while minimizing damage to the host cells. Upon in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
activation with the pharmacological agent phorbol myristate acetate
12-O-Tetradecanoylphorbol-13-acetate
12-O-tetradecanoylphorbol-13-acetate , also commonly known as tetradecanoylphorbol acetate, tetradecanoyl phorbol acetate, and phorbol 12-myristate 13-acetate , is diester of phorbol and a potent tumor promoter often employed in biomedical research to activate the signal transduction enzyme protein...
(PMA), Interleukin 8
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
(IL-8) or lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
(LPS), neutrophils release granule proteins and chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
to form an extracellular fibril matrix known as NETs through an active process.
More recently, it has also been shown that not only bacteria but also pathogenic fungi such as Candida albicans
Candida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...
induces neutrophils to form NETs that capture and kill C. albicans hyphal as well as yeast-form cells. NETs have also been documented in association with Plasmodium falciparum infections in children. NETs disarm pathogens with antimicrobial proteins such as neutrophil elastase and histones that are bound to the DNA. NETs provide for a high local concentration of antimicrobial components and bind, disarm, and kill microbes extracellularly independent of phagocytic uptake. In addition to their antimicrobial properties, NETs may serve as a physical barrier that prevents further spread of the pathogens. Furthermore, delivering the granule proteins into NETs may keep potentially injurious proteins like proteases from diffusing away and inducing damage in tissue adjacent to the site of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. NETs might also have a deleterious effect on the host, because the exposure of extracellular histone complexes could play a role during the development of autoimmune diseases like lupus erythematosus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
. NETs could also play a role in inflammatory diseases, as NETs could be identified in preeclampsia, a pregnancy related inflammatory disorder in which neutrophils are known to be activated. NETs also have been shown to be associated with the production of IgG antinuclear double stranded DNA antibodies in children infected with falciparum malaria.
High-resolution scanning electron microscopy has shown that NETs consist of stretches of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
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 . However, under flow conditions, NETs can form much larger structures, hundreds of nanometers in length and width.
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 blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s during sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
(specifically in the lung capillaries and liver sinusoid
Liver sinusoid
A liver sinusoid is a type of sinusoidal blood vessel that serves as a location for the oxygen-rich blood from the hepatic artery and the nutrient-rich blood from the portal vein....
s). Intra-vascular NET formation is tightly controlled and is regulated by platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s, which sense severe infection via platelet TLR4 and then bind to and activate neutrophils to form NETs. Platelet-induced NET formation occurs very rapidly (in minutes) and does not result in death of the neutrophils. 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
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and intravital microscopy demonstrated that bacterial trapping occurs in the liver sinusoids and lung capillaries (sites where platelets bind neutrophils)
These observations suggest that NETs might play an important role in the pathogenesis of infectious and inflammatory disorders.