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59-759: Neutrophils are a type of phagocytic white blood cell and part of innate immunity . More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different animals. They are also known as neutrocytes, heterophils or polymorphonuclear leukocytes. They are formed from stem cells in the bone marrow and differentiated into subpopulations of neutrophil-killers and neutrophil-cagers. They are short-lived (between 5 and 135 hours, see § Life span ) and highly mobile, as they can enter parts of tissue where other cells/molecules cannot. Neutrophils may be subdivided into segmented neutrophils and banded neutrophils (or bands ). They form part of

118-526: A broad range of proteins. Neutrophils have three methods for directly attacking microorganisms: phagocytosis (ingestion), degranulation (release of soluble anti-microbials), and generation of neutrophil extracellular traps (NETs). Neutrophils are phagocytes , capable of ingesting microorganisms or particles. For targets to be recognized, they must be coated in opsonins  – a process known as antibody opsonization . They can internalize and kill many microbes , each phagocytic event resulting in

177-482: A characteristic lobed appearance, the separate lobes connected by chromatin . The nucleolus disappears as the neutrophil matures, which is something that happens in only a few other types of nucleated cells. Up to 17% of female human neutrophil nuclei have a drumstick-shaped appendage which contains the inactivated X chromosome . In the cytoplasm, the Golgi apparatus is small, mitochondria and ribosomes are sparse, and

236-407: A focus of infection , attracted by cytokines expressed by activated endothelium , mast cells , and macrophages . Neutrophils express and release cytokines, which in turn amplify inflammatory reactions by several other cell types. In addition to recruiting and activating other cells of the immune system, neutrophils play a key role in the front-line defense against invading pathogens, and contain

295-438: A medical potential in treatment of certain forms of autoimmune disorders. Phagocytosis is used by many protists as a means of feeding, thus constituting phagotrophy. As in phagocytic immune cells, the resulting phagosome may be merged with lysosomes ( food vacuoles ) containing digestive enzymes , forming a phagolysosome . The food particles will then be digested, and the released nutrients are diffused or transported into

354-484: A mutation in the pyrin (or marenostrin ) gene, which is expressed mainly in neutrophil granulocytes, leads to a constitutively active acute-phase response and causes attacks of fever , arthralgia , peritonitis , and – eventually – amyloidosis . Hyperglycemia can lead to neutrophil dysfunction. Dysfunction in the neutrophil biochemical pathway myeloperoxidase as well as reduced degranulation are associated with hyperglycemia. The Absolute neutrophil count (ANC)

413-400: A nucleus divided into 2–5 lobes. Neutrophils are a type of phagocyte and are normally found in the bloodstream . During the beginning ( acute ) phase of inflammation , particularly as a result of bacterial infection , environmental exposure, and some cancers, neutrophils are one of the first responders of inflammatory cells to migrate toward the site of inflammation. They migrate through

472-676: A particularly important role for NETs in sepsis , where NETs are formed within blood vessels. Finally, NET formation has been demonstrated to augment macrophage bactericidal activity during infection. Recently, NETs have been shown to play a role in inflammatory diseases, as NETs could be detected in preeclampsia , a pregnancy-related inflammatory disorder in which neutrophils are known to be activated. Neutrophil NET formation may also impact cardiovascular disease , as NETs may influence thrombus formation in coronary arteries . NETs are now known to exhibit pro- thrombotic effects both in vitro and in vivo . More recently, in 2020 NETs were implicated in

531-460: A process called degranulation . The contents of these granules have antimicrobial properties, and help combat infection. Glitter cells are polymorphonuclear leukocyte neutrophils with granules. In 2004, Brinkmann and colleagues described a striking observation that activation of neutrophils causes the release of web-like structures of DNA; this represents a third mechanism for killing bacteria. These neutrophil extracellular traps (NETs) comprise

590-452: A property of leucocytes, the immune cells, was from the German zoologist Ernst Haeckel . Haeckel discovered that blood cells of sea slug, Tethys , could ingest Indian ink (or indigo ) particles. It was the first direct evidence of phagocytosis by immune cells. Haeckel reported his experiment in a 1862 monograph Die Radiolarien (Rhizopoda Radiaria): Eine Monographie. Phagocytosis

649-403: A reactive oxygen species. Superoxide decays spontaneously or is broken down via enzymes known as superoxide dismutases (Cu/ZnSOD and MnSOD), to hydrogen peroxide, which is then converted to hypochlorous acid (HClO), by the green heme enzyme myeloperoxidase . It is thought that the bactericidal properties of HClO are enough to kill bacteria phagocytosed by the neutrophil, but this may instead be

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708-459: A second signal from pattern recognition receptors (PRRs) activated by attachment to pathogen-associated molecular patterns (PAMPS), which leads to NF-κB activation. Fcγ receptors recognise IgG coated targets. The main recognised part is the Fc fragment . The molecule of the receptor contain an intracellular ITAM domain or associates with an ITAM-containing adaptor molecule. ITAM domains transduce

767-457: A standard normal range. People of African and Middle Eastern descent may have lower counts, which are still normal. A report may divide neutrophils into segmented neutrophils and bands . When circulating in the bloodstream and inactivated, neutrophils are spherical. Once activated, they change shape and become more amorphous or amoeba -like and can extend pseudopods as they hunt for antigens . The capacity of neutrophils to engulf bacteria

826-644: A step necessary for the activation of proteases. Though neutrophils can kill many microbes, the interaction of neutrophils with microbes and molecules produced by microbes often alters neutrophil turnover. The ability of microbes to alter the fate of neutrophils is highly varied, can be microbe-specific, and ranges from prolonging the neutrophil lifespan to causing rapid neutrophil lysis after phagocytosis. Chlamydia pneumoniae and Neisseria gonorrhoeae have been reported to delay neutrophil apoptosis . Thus, some bacteria – and those that are predominantly intracellular pathogens – can extend

885-433: A surface, neutrophil granulocytes have an average diameter of 12–15  micrometers (μm) in peripheral blood smears . In suspension, human neutrophils have an average diameter of 8.85 μm. With the eosinophil and the basophil , they form the class of polymorphonuclear cells , named for the nucleus ' multilobulated shape (as compared to lymphocytes and monocytes , the other types of white cells). The nucleus has

944-428: A web of fibers composed of chromatin and serine proteases that trap and kill extracellular microbes. It is suggested that NETs provide a high local concentration of antimicrobial components and bind, disarm, and kill microbes independent of phagocytic uptake. In addition to their possible antimicrobial properties, NETs may serve as a physical barrier that prevents further spread of pathogens. Trapping of bacteria may be

1003-407: A wide variety of anti-microbial defensins that fuse with phagocytic vacuoles . Azurophils may contain myeloperoxidase , phospholipase A2 , acid hydrolases , elastase , defensins, neutral serine proteases , bactericidal permeability-increasing protein , lysozyme , cathepsin G , proteinase 3 , and proteoglycans . Azurophil granules are also known as "primary granules". Furthermore,

1062-432: Is 28:1:25. Neutrophils are much more numerous than the longer-lived monocyte / macrophage phagocytes. A pathogen (disease-causing microorganism or virus) is likely to first encounter a neutrophil. Some experts hypothesize that the short lifetime of neutrophils is an evolutionary adaptation. The short lifetime of neutrophils minimizes propagation of those pathogens that parasitize phagocytes (e.g. Leishmania ) because

1121-421: Is also used in diagnosis and prognosis. ANC is the gold standard for determining severity of neutropenia, and thus neutropenic fever. Any ANC < 1500 cells / mm is considered neutropenia, but <500 cells / mm is considered severe. There is also new research tying ANC to myocardial infarction as an aid in early diagnosis. Neutrophils promote ventricular tachycardia in acute myocardial infarction. In autopsy ,

1180-502: Is highly microbicidal. Monocytes, and the macrophages that mature from them, leave blood circulation to migrate through tissues. There they are resident cells and form a resting barrier. Macrophages initiate phagocytosis by mannose receptors , scavenger receptors , Fcγ receptors and complement receptors 1, 3 and 4. Macrophages are long-lived and can continue phagocytosis by forming new lysosomes. Dendritic cells also reside in tissues and ingest pathogens by phagocytosis. Their role

1239-468: Is located on the αL integrin unit ( CD11a ). Two functionally unequal subpopulations of neutrophils were identified on the basis of different levels of their reactive oxygen metabolite generation, membrane permeability, activity of enzyme system, and ability to be inactivated. The cells of one subpopulation with high membrane permeability (neutrophil-killers) intensively generate reactive oxygen metabolites and are inactivated in consequence of interaction with

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1298-641: Is not killing or clearance of microbes, but rather breaking them down for antigen presentation to the cells of the adaptive immune system. Receptors for phagocytosis can be divided into two categories by recognised molecules. The first, opsonic receptors, are dependent on opsonins . Among these are receptors that recognise the Fc part of bound IgG antibodies, deposited complement or receptors, that recognise other opsonins of cell or plasma origin. Non-opsonic receptors include lectin-type receptors, Dectin receptor, or scavenger receptors. Some phagocytic pathways require

1357-604: Is old in evolutionary terms, being present even in invertebrates . Neutrophils , macrophages , monocytes , dendritic cells , osteoclasts and eosinophils can be classified as professional phagocytes. The first three have the greatest role in immune response to most infections. The role of neutrophils is patrolling the bloodstream and rapid migration to the tissues in large numbers only in case of infection. There they have direct microbicidal effect by phagocytosis. After ingestion, neutrophils are efficient in intracellular killing of pathogens. Neutrophils phagocytose mainly via

1416-410: Is reduced when simple sugars like glucose, fructose as well as sucrose, honey and orange juice were ingested, while the ingestion of starches had no effect. Fasting, on the other hand, strengthened the neutrophils' phagocytic capacity to engulf bacteria. It was concluded that the function, and not the number, of phagocytes in engulfing bacteria was altered by the ingestion of sugars. In 2007 researchers at

1475-426: Is used as a means of feeding and provides the organism part or all of its nourishment, it is called phagotrophy and is distinguished from osmotrophy , which is nutrition taking place by absorption. The history of phagocytosis represents the scientific establishment of immunology as the process is the first immune response mechanism discovered and understood as such. The earliest definitive account of cell eating

1534-608: The centrosome of the phagocyte and is fused with lysosomes , forming a phagolysosome and leading to degradation. Progressively, the phagolysosome is acidified, activating degradative enzymes. Degradation can be oxygen-dependent or oxygen-independent. Leukocytes generate hydrogen cyanide during phagocytosis, and can kill bacteria , fungi , and other pathogens by generating several other toxic chemicals. Some bacteria, for example Treponema pallidum , Escheria coli and Staphylococcus aureus , are able to avoid phagocytosis by several mechanisms. Following apoptosis ,

1593-431: The cytosol for use in other metabolic processes. Mixotrophy can involve phagotrophic nutrition and phototrophic nutrition. Azurophilic granule An azurophilic granule is a cellular object readily stainable with a Romanowsky stain . In white blood cells and hyperchromatin , staining imparts a burgundy or merlot coloration. Neutrophils in particular are known for containing azurophils loaded with

1652-522: The phosphoinositide 3-kinases ( PI3Ks ). In neutrophils, lipid products of PI3Ks regulate activation of Rac1, hematopoietic Rac2, and RhoG GTPases of the Rho family and are required for cell motility . Ras-GTPases and Rac-GTPases regulate cytoskeletal dynamics and facilitate neutrophils adhesion, migration, and spreading. They accumulate asymmetrically to the plasma membrane at the leading edge of polarized cells. Spatially regulating Rho GTPases and organizing

1711-411: The polymorphonuclear cells family (PMNs) together with basophils and eosinophils . The name neutrophil derives from staining characteristics on hematoxylin and eosin ( H&E ) histological or cytological preparations. Whereas basophilic white blood cells stain dark blue and eosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Normally, neutrophils contain

1770-518: The Fcγ receptors and complement receptors 1 and 3. The microbicidal effect of neutrophils is due to a large repertoire of molecules present in pre-formed granules. Enzymes and other molecules prepared in these granules are proteases, such as collagenase , gelatinase or serine proteases , myeloperoxidase , lactoferrin and antibiotic proteins. Degranulation of these into the phagosome, accompanied by high reactive oxygen species production (oxidative burst)

1829-570: The Whitehead Institute of Biomedical Research found that given a selection of sugars on microbial surfaces, the neutrophils reacted to some types of sugars preferentially. The neutrophils preferentially engulfed and killed beta-1,6-glucan targets compared to beta-1,3-glucan targets. The average lifespan of inactivated human neutrophils in the circulation has been reported by different approaches to be between 5 and 135 hours. Upon activation, they marginate (position themselves adjacent to

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1888-400: The blood smear and is positive when most or all of the neutrophils have 5 or more segments. Neutrophils are the most abundant white blood cells in the human body (approximately 10 are produced daily); they account for approximately 50–70% of all white blood cells (leukocytes). The stated normal range for human blood counts varies between laboratories, but a neutrophil count of 2.5–7.5 × 10/L is

1947-413: The blood vessel endothelium) and undergo selectin -dependent capture followed by integrin -dependent adhesion in most cases, after which they migrate into tissues, where they survive for 1–2 days. Neutrophils have also been demonstrated to be released into the blood from a splenic reserve following myocardial infarction . The distribution ratio of neutrophils in bone marrow, blood and connective tissue

2006-401: The blood vessels and then through interstitial space, following chemical signals such as interleukin-8 (IL-8), C5a , fMLP , leukotriene B4 , and hydrogen peroxide (H 2 O 2 ) in a process called chemotaxis . They are the predominant cells in pus , accounting for its whitish/yellowish appearance. Neutrophils are recruited to the site of injury within minutes following trauma and are

2065-404: The cell surface are involved in this process. Neutrophils undergo a process called chemotaxis via amoeboid movement , which allows them to migrate toward sites of infection or inflammation. Cell surface receptors allow neutrophils to detect chemical gradients of molecules such as interleukin-8 (IL-8), interferon gamma (IFN-γ), C3a, C5a , and leukotriene B4 , which these cells use to direct

2124-503: The cell surface of the macrophage such as the phosphatidylserine receptor or by soluble (free-floating) receptors such as thrombospondin 1 , GAS6 , and MFGE8 , which themselves then bind to other receptors on the macrophage such as CD36 and alpha-v beta-3 integrin . Defects in apoptotic cell clearance is usually associated with impaired phagocytosis of macrophages. Accumulation of apoptotic cell remnants often causes autoimmune disorders; thus pharmacological potentiation of phagocytosis has

2183-478: The dying cells need to be taken up into the surrounding tissues by macrophages in a process called efferocytosis . One of the features of an apoptotic cell is the presentation of a variety of intracellular molecules on the cell surface, such as calreticulin , phosphatidylserine (from the inner layer of the plasma membrane), annexin A1 , oxidised LDL and altered glycans . These molecules are recognised by receptors on

2242-409: The enzyme in extracellular space. Unregulated activity of neutrophil elastase can lead to disruption of pulmonary barrier showing symptoms corresponding with acute lung injury . The enzyme also influences activity of macrophages by cleaving their toll-like receptors (TLRs) and downregulating cytokine expression by inhibiting nuclear translocation of NF-κB . In Familial Mediterranean fever (FMF),

2301-498: The footpad path of LysM-eGFP mice 20 minutes after infection with Listeria monocytogenes . Phagocytosis In a multicellular organism's immune system , phagocytosis is a major mechanism used to remove pathogens and cell debris. The ingested material is then digested in the phagosome. Bacteria, dead tissue cells, and small mineral particles are all examples of objects that may be phagocytized. Some protozoa use phagocytosis as means to obtain nutrients. Where phagocytosis

2360-408: The formation of a phagosome into which reactive oxygen species and hydrolytic enzymes are secreted. The consumption of oxygen during the generation of reactive oxygen species has been termed the " respiratory burst ", although unrelated to respiration or energy production. The respiratory burst involves the activation of the enzyme NADPH oxidase , which produces large quantities of superoxide ,

2419-468: The formation of blood clots in cases of severe COVID-19 . TANs can exhibit an elevated extracellular acidification rate when there is an increase in glycolysis levels. When there is a metabolic shift in TANs this can lead to tumor progression in certain areas of the body, such as the lungs. TANs support the growth and progression of tumors unlike normal neutrophils which would inhibit tumor progression through

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2478-444: The hallmark of acute inflammation. They not only play a central role in combating infection but also contribute to pain in the acute period by releasing pro-inflammatory cytokines and other mediators that sensitize nociceptors, leading to heightened pain perception. However, due to some pathogens being indigestible, they may not be able to resolve certain infections without the assistance of other types of immune cells. When adhered to

2537-494: The leading edge of the cell, PI3Ks and their lipid products could play pivotal roles in establishing leukocyte polarity, as compass molecules that tell the cell where to crawl. It has been shown in mice that in certain conditions neutrophils have a specific type of migration behaviour referred to as neutrophil swarming during which they migrate in a highly coordinated manner and accumulate and cluster to sites of inflammation. Being highly motile , neutrophils quickly congregate at

2596-452: The low affinity Fc-γ receptor IIIb (FCGR3B : CD16b ) The single known HNA-2a antigen is located on CD177 . The HNA-3 antigen system has two antigens (3a and 3b) which are located on the seventh exon of the CLT2 gene ( SLC44A2 ). The HNA-4 and HNA-5 antigen systems each have two known antigens (a and b) and are located in the β2 integrin . HNA-4 is located on the αM chain ( CD11b ) and HNA-5

2655-408: The mannose receptor. Eight lectin-like domains form the extracellular part of the receptor. The ingestion mediated by the mannose receptor is distinct in molecular mechanisms from Fcγ receptor or complement receptor mediated phagocytosis. Engulfment of material is facilitated by the actin-myosin contractile system. The phagosome is the organelle formed by phagocytosis of material. It then moves toward

2714-404: The more time such parasites spend outside a host cell , the more likely they will be destroyed by some component of the body's defenses. Also, because neutrophil antimicrobial products can also damage host tissues , their short life limits damage to the host during inflammation . Neutrophils will be removed after phagocytosis of pathogens by macrophages. PECAM-1 and phosphatidylserine on

2773-450: The neutrophil lifespan by disrupting the normal process of spontaneous apoptosis and/or PICD (phagocytosis-induced cell death). On the other end of the spectrum, some pathogens such as Streptococcus pyogenes are capable of altering neutrophil fate after phagocytosis by promoting rapid cell lysis and/or accelerating apoptosis to the point of secondary necrosis. Neutrophils also release an assortment of proteins in three types of granules by

2832-485: The osteoblasts can promote bone growth thus forming a favorable environment for tumor cells to grow to form bone metastasis. Low neutrophil counts are termed neutropenia . This can be congenital (developed at or before birth) or it can develop later, as in the case of aplastic anemia or some kinds of leukemia . It can also be a side-effect of medication , most prominently chemotherapy . Neutropenia makes an individual highly susceptible to infections. It can also be

2891-478: The path of their migration. Neutrophils have a variety of specific receptors, including ones for complement , cytokines like interleukins and IFN-γ, chemokines , lectins , and other proteins. They also express receptors to detect and adhere to endothelium and Fc receptors for opsonin . In leukocytes responding to a chemoattractant , the cellular polarity is regulated by activities of small Ras or Rho guanosine triphosphatases (Ras or Rho GTPases ) and

2950-438: The phagocytosis of tumor cells. Utilizing a mouse model, they identified that both Glut1 and glucose metabolism increased in TANs found within a mouse who possessed lung adenocarcinoma. A study showed that lung tumor cells can remotely initiate osteoblasts and these osteoblasts can worsen tumors in two ways. First, they can induce SiglecF-expressing neutrophil formation that in turn promotes lung tumor growth and progression. Second,

3009-696: The presence of neutrophils in the heart or brain is one of the first signs of infarction, and is useful in the timing and diagnosis of myocardial infarction and stroke . Just like phagocytes, pathogens may evade or infect neutrophils. Some bacterial pathogens evolved various mechanisms such as virulence molecules to avoid being killed by neutrophils. These molecules collectively may alter or disrupt neutrophil recruitment, apoptosis or bactericidal activity. Neutrophils can also serve as host cell for various parasites that infects them avoding phagocytosis, including: There are five (HNA 1–5) sets of neutrophil antigens recognized. The three HNA-1 antigens (a-c) are located on

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3068-496: The receptors contains a lectin-like complement-binding domain. Recognition by complement receptors is not enough to cause internalisation without additional signals. In macrophages, the CR1 , CR3 and CR4 are responsible for recognition of targets. Complement coated targets are internalised by 'sinking' into the phagocyte membrane, without any protrusions. Mannose and other pathogen-associated sugars, such as fucose , are recognised by

3127-460: The result of colonization by intracellular neutrophilic parasites. In alpha 1-antitrypsin deficiency , the important neutrophil elastase is not adequately inhibited by alpha 1-antitrypsin , leading to excessive tissue damage in the presence of inflammation – the most prominent one being emphysema . Negative effects of elastase have also been shown in cases when the neutrophils are excessively activated (in otherwise healthy individuals) and release

3186-410: The rough endoplasmic reticulum is absent. The cytoplasm also contains about 200 granules, of which a third are azurophilic . Neutrophils will show increasing segmentation (many segments of the nucleus) as they mature. A normal neutrophil should have 3–5 segments. Hypersegmentation is not normal but occurs in some disorders, most notably vitamin B 12 deficiency . This is noted in a manual review of

3245-481: The signal from the surface of the phagocyte to the nucleus. For example, activating receptors of human macrophages are FcγRI , FcγRIIA , and FcγRIII . Fcγ receptor mediated phagocytosis includes formation of protrusions of the cell called a 'phagocytic cup' and activates an oxidative burst in neutrophils. These receptors recognise targets coated in C3b , C4b and C3bi from plasma complement. The extracellular domain of

3304-413: The substrate, whereas cells of another subpopulation (neutrophil-cagers) produce reactive oxygen species less intensively, don't adhere to substrate and preserve their activity. Additional studies have shown that lung tumors can be infiltrated by various populations of neutrophils. Neutrophils display highly directional amoeboid motility in infected footpad and phalanges. Intravital imaging was performed in

3363-437: The term "azurophils" may refer to a unique type of cells, identified only in reptiles . These cells are similar in size to so-called heterophils with abundant cytoplasm that is finely to coarsely granular and may sometimes contain vacuoles. Granules may impart a purplish hue to the cytoplasm, particularly to the outer region. Occasionally, azurophils are observed with vacuolated cytoplasm. This hematology article

3422-514: Was given by Swiss scientist Albert von Kölliker in 1849. In his report in Zeitschrift für Wissenschaftliche Zoologie, Kölliker described the feeding process of an amoeba-like alga, Actinophyrys sol (a heliozoan ) mentioning details of how the protist engulfed and swallowed (the process now called endocytosis) a small organism, that he named infusoria (a generic name for microbes at the time). The first demonstration of phagocytosis as

3481-493: Was noted by Canadian physician William Osler (1876), and later studied and named by Élie Metchnikoff (1880, 1883). Phagocytosis is one main mechanisms of the innate immune defense. It is one of the first processes responding to infection , and is also one of the initiating branches of an adaptive immune response. Although most cells are capable of phagocytosis, some cell types perform it as part of their main function. These are called 'professional phagocytes.' Phagocytosis

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