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.) Neutrophil Extracellular Traps.png
A scanning electron microscope image of NETs engulfing fungal cells ( Candida albicans ) in an infected mouse lung. (Click on image for more details.)
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. Agregation of neutrophils around spontaneously activated netosis observed in Alzheimers' Desease patients blood.jpg
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 extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens. [2] Neutrophils are the immune system's first line of defense against infection and have conventionally been thought to kill invading pathogens through two strategies: engulfment of microbes and secretion of anti-microbials. In 2004, a novel third function was identified: formation of NETs. NETs allow neutrophils to kill extracellular pathogens while minimizing damage to the host cells. [3] 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 NET through an active process. [2]

Contents

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 neutrophil elastase, cathepsin G and histones that have a high affinity for DNA. [6] 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. 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 blood vessels during sepsis (specifically in the lung capillaries and liver sinusoids). Intra-vascular NET formation is tightly controlled and is regulated by platelets, 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 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 NADPH oxidase activation of protein-arginine deiminase 4 (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 apoptosis or necrosis. [14] In suicidal NETosis, the intracellular NET formation is followed by the rupture of the plasma membrane, releasing it into the extracellular space. This NETosis pathway can be initiated through activation of toll-like receptors (TLRs), Fc receptors, and complement receptors with various ligands such as 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 TLR2 ligands." [12] Vital NETosis is made possible through the 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 lipoxygenase pathway – during certain forms of activation (including contact with bacteria) neutrophil 5-lipoxygenase forms 5-HETE-phospholipids that inhibit NET formation. [16] Evidence from laboratory experiments suggests that NETs are cleaned away by 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 autoimmune diseases like systemic lupus erythematosus (SLE). [18] 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. [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 JAMA Cardiology suggested that NETs played a major role in COVID-19 patients who developed ST-elevation myocardial infarctions. [33]

Related Research Articles

<span class="mw-page-title-main">Platelet</span> Component of blood aiding in coagulation

Platelets or thrombocytes are a component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot. Platelets have no cell nucleus; they are fragments of cytoplasm derived from the megakaryocytes of the bone marrow or lung, which then enter the circulation. Platelets are found only in mammals, whereas in other vertebrates, thrombocytes circulate as intact mononuclear cells.

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Neutrophil</span> Most abundant type of granulocytes and the most abundant white blood cell

Neutrophils are a type of white blood cell. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in different animals.

<span class="mw-page-title-main">Phagocyte</span> Cells that ingest harmful matter within the body

Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.

<span class="mw-page-title-main">Granulocyte</span> Category of white blood cells

Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that is, they have varying shapes (morphology) of the nucleus ; and are referred to as polymorphonuclear leukocytes. In common terms, polymorphonuclear granulocyte refers specifically to "neutrophil granulocytes", the most abundant of the granulocytes; the other types have varying morphology. Granulocytes are produced via granulopoiesis in the bone marrow.

Granzymes are serine proteases released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target cell, thus eliminating cells that have become cancerous or are infected with viruses or bacteria. Granzymes also kill bacteria and inhibit viral replication. In NK cells and T cells, granzymes are packaged in cytotoxic granules along with perforin. Granzymes can also be detected in the rough endoplasmic reticulum, golgi complex, and the trans-golgi reticulum. The contents of the cytotoxic granules function to permit entry of the granzymes into the target cell cytosol. The granules are released into an immune synapse formed with a target cell, where perforin mediates the delivery of the granzymes into endosomes in the target cell, and finally into the target cell cytosol. Granzymes are part of the serine esterase family. They are closely related to other immune serine proteases expressed by innate immune cells, such as neutrophil elastase and cathepsin G.

<span class="mw-page-title-main">Myeloperoxidase deficiency</span> Medical condition

Myeloperoxidase deficiency is a disorder featuring lack in either the quantity or the function of myeloperoxidase–an iron-containing protein expressed primarily in neutrophil granules. There are two types of myeloperoxidase deficiency: primary/inherited and secondary/acquired. Lack of functional myeloperoxidase leads to less efficient killing of intracellular pathogens, particularly Candida albicans, as well as less efficient production and release of neutrophil extracellular traps (NETs) from the neutrophils to trap and kill extracellular pathogens. Despite these characteristics, more than 95% of individuals with myeloperoxidase deficiency experience no symptoms in their lifetime. For those who do experience symptoms, the most common symptom is frequent infections by Candida albicans. Individuals with myeloperoxidase deficiency also experience higher rates of chronic inflammatory conditions. Myeloperoxidase deficiency is diagnosed using flow cytometry or cytochemical stains. There is no treatment for myeloperoxidase deficiency itself. Rather, in the rare cases that individuals experience symptoms, these infections should be treated.

<span class="mw-page-title-main">Phagosome</span>

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).

<span class="mw-page-title-main">Innate immune system</span> Immunity strategy in living beings

The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.

<span class="mw-page-title-main">P-selectin</span> Type-1 transmembrane protein

P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.

<span class="mw-page-title-main">Platelet factor 4</span> Protein involved in blood clotting, wound healing and inflammation

Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is also known as chemokine ligand 4 (CXCL4). This chemokine is released from alpha-granules of activated platelets during platelet aggregation, and promotes blood coagulation by moderating the effects of heparin-like molecules. Due to these roles, it is predicted to play a role in wound repair and inflammation. It is usually found in a complex with proteoglycan.

<span class="mw-page-title-main">Cathepsin G</span> Protein-coding gene in the species Homo sapiens

Cathepsin G is a protein that in humans is encoded by the CTSG gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response.

<span class="mw-page-title-main">Degranulation</span> Process by which cells lose secretory granules

Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

A non-specific immune cell is an immune cell that responds to many antigens, not just one antigen. Non-specific immune cells function in the first line of defense against infection or injury. The innate immune system is always present at the site of infection and ready to fight the bacteria; it can also be referred to as the "natural" immune system. The cells of the innate immune system do not have specific responses and respond to each foreign invader using the same mechanism.

Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger signals, and alarmins because they serve as warning signs to alert the organism to any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen. Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern recognition receptor. Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process. As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α. In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns initiate and perpetuate the infectious pathogen-induced inflammatory response. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury. This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function. Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.

<span class="mw-page-title-main">Inflammasome</span> Cytosolic multiprotein complex that mediates the activation of Caspase 1

Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of gasdermin D. The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane. Additionally, inflammasomes can be incorporated into larger cell death-inducing complexes called PANoptosomes, which drive another distinct form of pro-inflammatory cell death called PANoptosis.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

Immunogenic cell death is any type of cell death eliciting an immune response. Both accidental cell death and regulated cell death can result in immune response. Immunogenic cell death contrasts to forms of cell death that do not elicit any response or even mediate immune tolerance.

Candidalysin is a cytolytic 31-amino acid α-helical amphipathic peptide toxin secreted by the opportunistic pathogen Candida albicans. This toxin is a fungal example of a classical virulence factor. Hyphal morphogenesis in C. albicans is associated with damage to host epithelial cells; during this process Candidalysin is released and intercalates in host membranes. Candidalysin promotes damage of oral epithelial cells and induces lactate dehydrogenase release and calcium ion influx. It is unique in the fact that it is the first peptide toxin to be identified in any human fungal pathogen.

<span class="mw-page-title-main">Arturo Zychlinsky</span> Biologist

Arturo Zychlinsky is a biologist and since 2001 director at the Max Planck Institute for Infection Biology. His research focuses on Neutrophil Extracellular Traps (NETs) which he discovered together with Volker Brinkmann, and the immune function of chromatin.

References

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  27. ↑ Laridan, Elodie; Denorme, Frederik; Desender, Linda; François, Olivier; Andersson, Tommy; Deckmyn, Hans; Vanhoorelbeke, Karen; De Meyer, Simon F. (August 2, 2017). "Neutrophil extracellular traps in ischemic stroke thrombi". Annals of Neurology. 82 (2): 223–232. doi:10.1002/ana.24993. PMID   28696508. S2CID   205347011.
  28. ↑ Ducroux, Celina; Di Meglio, Lucas; Loyau, Stephane; Delbosc, Sandrine; Boisseau, William; Deschildre, Catherine; Ben Maacha, Malek; Blanc, Raphael; Redjem, Hocine; Ciccio, Gabriele; Smajda, Stanislas; Fahed, Robert; Michel, Jean-Baptiste; Piotin, Michel; Salomon, Laurence; Mazighi, Mikael; Ho-Tin-Noe, Benoit; Desilles, Jean-Philippe (March 2, 2018). "Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke". Stroke. 49 (3): 754–757. doi: 10.1161/STROKEAHA.117.019896 . PMID   29438080.
  29. ↑ Vallés, Juana; Lago, Aída; Santos, María Teresa; Latorre, Ana María; Tembl, José I.; Salom, Juan B.; Nieves, Candela; Moscardó, Antonio (October 5, 2017). "Neutrophil extracellular traps are increased in patients with acute ischemic stroke: prognostic significance". Thrombosis and Haemostasis. 117 (10): 1919–1929. doi:10.1160/TH17-02-0130. PMID   28837206. S2CID   21968805.
  30. ↑ Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD (Sep 7, 2010). "Extracellular DNA traps promote thrombosis". Proc Natl Acad Sci U S A. 107 (36): 15880–5. Bibcode:2010PNAS..10715880F. doi: 10.1073/pnas.1005743107 . PMC   2936604 . PMID   20798043.
  31. ↑ Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD (Nov 1, 2011). "Neutrophil Extracellular Traps Promote Deep Vein Thrombosis in Mice". Journal of Thrombosis and Haemostasis. 10 (1): 136–144. doi:10.1111/j.1538-7836.2011.04544.x. PMC   3319651 . PMID   22044575.
  32. ↑ Borissoff, JI; ten Cate, H (September 2011). "From neutrophil extracellular traps release to thrombosis: an overshooting host-defense mechanism?". Journal of Thrombosis and Haemostasis. 9 (9): 1791–4. doi: 10.1111/j.1538-7836.2011.04425.x . PMID   21718435. S2CID   5368241.
  33. ↑ Blasco, Ana; Coronado, María-José; Hernández-Terciado, Fernando; Martín, Paloma; Royuela, Ana; Ramil, Elvira; García, Diego; Goicolea, Javier; Del Trigo, María; Ortega, Javier; Escudier, Juan M. (2020-12-29). "Assessment of Neutrophil Extracellular Traps in Coronary Thrombus of a Case Series of Patients With COVID-19 and Myocardial Infarction". JAMA Cardiology. 6 (4): 1–6. doi: 10.1001/jamacardio.2020.7308 . ISSN   2380-6583. PMC   7772744 . PMID   33372956.
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