| Neutrophil | |
|---|---|
.png) 3D rendering of a neutrophil | |
 Neutrophils with segmented nuclei surrounded byerythrocytes andplatelets. Intra-cellular granules are visible in thecytoplasm (Giemsa stained). | |
| Details | |
| System | Immune system |
| Function | Phagocytosis |
| Identifiers | |
| MeSH | D009504 |
| TH | H2.00.04.1.02012 |
| FMA | 62860 |
| Anatomical terms of microanatomy | |
Neutrophils are a type ofphagocyticwhite blood cell and part ofinnate immunity. More specifically, they form the most abundant type ofgranulocytes and make up 40% to 70% of all white blood cells in humans.[1] Their functions vary in different animals.[2] They are also known as neutrocytes, heterophils or polymorphonuclear leukocytes.
They are formed fromstem cells in thebone marrow anddifferentiated intosubpopulations 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 (orbands). They form part of thepolymorphonuclear cells family (PMNs) together withbasophils andeosinophils.[3][4][5]
The nameneutrophil derives from staining characteristics onhematoxylin andeosin (H&E)histological orcytological preparations. Whereasbasophilic white blood cells stain dark blue andeosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Normally, neutrophils contain a nucleus divided into 2–5 lobes.[6]
Neutrophils are a type ofphagocyte and are normally found in thebloodstream. During the beginning (acute) phase ofinflammation, particularly as a result ofbacterialinfection, environmental exposure,[7] and some cancers,[8][9] neutrophils are one of the first responders of inflammatory cells to migrate toward the site of inflammation. They migrate through the blood vessels and then throughinterstitial space, following chemical signals such asinterleukin-8 (IL-8),C5a,fMLP,leukotriene B4, andhydrogen peroxide (H2O2)[10] in a process calledchemotaxis. They are the predominant cells inpus, accounting for its whitish/yellowish appearance.[11]
Neutrophils are recruited to the site of injury within minutes following trauma and are the hallmark of acute inflammation.[12] 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 sensitizenociceptors, leading to heightened pain perception.[13] However, due to somepathogens being indigestible, they may not be able to resolve certain infections without the assistance of other types of immune cells.
When adhered to a surface, neutrophil granulocytes have an average diameter of 12–15 micrometers (μm) inperipheral blood smears. In suspension, human neutrophils have an average diameter of 8.85 μm.[14]
With theeosinophil and thebasophil, they form the class ofpolymorphonuclear cells, named for thenucleus' multilobulated shape (as compared tolymphocytes andmonocytes, the other types of white cells). The nucleus has a characteristic lobed appearance, the separate lobes connected bychromatin. The nucleolus disappears as the neutrophil matures, which is something that happens in only a few other types of nucleated cells.[15]: 168 Up to 17% of female human neutrophil nuclei have a drumstick-shaped appendage which contains theinactivated X chromosome.[16] In the cytoplasm, theGolgi apparatus is small,mitochondria andribosomes are sparse, and the roughendoplasmic reticulum is absent.[15]: 170 The cytoplasm also contains about 200 granules, of which a third areazurophilic.[15]: 170
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 notablyvitamin B12 deficiency. This is noted in a manual review of the blood smear and is positive when most or all of the neutrophils have 5 or more segments.[citation needed]
Neutrophils are the most abundant white blood cells in the human body (approximately 1011 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 × 109/L is a standard normal range. People ofAfrican andMiddle Eastern descent may have lower counts, which are still normal.[17] A report may divide neutrophils into segmented neutrophils andbands.
When circulating in the bloodstream and inactivated, neutrophils are spherical. Once activated, they change shape and become more amorphous oramoeba-like and can extendpseudopods as they hunt forantigens.[18]
The capacity of neutrophils to engulf bacteria 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.[19] In 2007 researchers at 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.[20][21]
The average lifespan of inactivated human neutrophils in the circulation has been reported by different approaches to be between 5 and 135 hours.[22][23]
Upon activation, they marginate (position themselves adjacent to the blood vessel endothelium) and undergoselectin-dependent capture followed byintegrin-dependent adhesion in most cases, after which they migrate into tissues, where they survive for 1–2 days.[24] Neutrophils have also been demonstrated to be released into the blood from asplenic reserve followingmyocardial infarction.[25]
The distribution ratio of neutrophils in bone marrow, blood and connective tissue is 28:1:25.[citation needed]
Neutrophils are much more numerous than the longer-livedmonocyte/macrophage phagocytes. Apathogen (disease-causing microorganism or virus) is likely to first encounter a neutrophil. Some experts hypothesize that the short lifetime of neutrophils is anevolutionary adaptation. The short lifetime of neutrophils minimizes propagation of those pathogens thatparasitize phagocytes (e.g.Leishmania[26]) because the more time such parasites spend outside a hostcell, the more likely they will be destroyed by some component of the body's defenses. Also, because neutrophilantimicrobial products can also damage hosttissues, their short life limits damage to the host duringinflammation.[24]
Neutrophils will be removed afterphagocytosis of pathogens by macrophages.PECAM-1 andphosphatidylserine on the cell surface are involved in this process.[citation needed]
Neutrophils undergo a process calledchemotaxis viaamoeboid movement, which allows them to migrate toward sites of infection or inflammation. Cell surface receptors allow neutrophils to detect chemical gradients of molecules such asinterleukin-8 (IL-8),interferon gamma (IFN-γ), C3a,C5a, andleukotriene B4, which these cells use to direct the path of their migration.[citation needed]
Neutrophils have a variety of specific receptors, including ones forcomplement, cytokines likeinterleukins and IFN-γ,chemokines,lectins, and other proteins. They also express receptors to detect and adhere toendothelium andFc receptors foropsonin.[27]
In leukocytes responding to achemoattractant, thecellular polarity is regulated by activities of small Ras orRhoguanosine triphosphatases (Ras orRho GTPases) and thephosphoinositide 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 forcell motility. Ras-GTPases andRac-GTPases regulate cytoskeletal dynamics and facilitate neutrophils adhesion, migration, and spreading.[28][29][30] They accumulate asymmetrically to theplasma membrane at the leading edge of polarized cells. Spatially regulating Rho GTPases and organizing 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.[citation needed]
It has been shown in mice that in certain conditions neutrophils have a specific type of migration behaviour referred to asneutrophil swarming during which they migrate in a highly coordinated manner and accumulate and cluster to sites of inflammation.[31]
Being highlymotile, neutrophils quickly congregate at a focus ofinfection, attracted bycytokines expressed by activatedendothelium,mast cells, andmacrophages. Neutrophils express[32] and release cytokines, which in turn amplify inflammatory reactions by several other cell types.[citation needed]
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 a broad range of proteins.[33] Neutrophils have three methods for directly attacking microorganisms:phagocytosis (ingestion),degranulation (release of soluble anti-microbials), and generation ofneutrophil extracellular traps (NETs).[34]
Neutrophils arephagocytes, capable of ingesting microorganisms or particles. For targets to be recognized, they must be coated inopsonins – a process known asantibody opsonization.[18] They can internalize and kill manymicrobes, each phagocytic event resulting in the formation of aphagosome into whichreactive 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.[citation needed]
The respiratory burst involves the activation of theenzymeNADPH oxidase, which produces large quantities ofsuperoxide, a reactive oxygen species. Superoxide decays spontaneously or is broken down via enzymes known assuperoxide dismutases (Cu/ZnSOD and MnSOD), to hydrogen peroxide, which is then converted tohypochlorous acid (HClO), by the green heme enzymemyeloperoxidase. It is thought that the bactericidal properties of HClO are enough to kill bacteria phagocytosed by the neutrophil, but this may instead be a step necessary for the activation of proteases.[35]
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 neutrophillysis after phagocytosis.Chlamydia pneumoniae andNeisseria gonorrhoeae have been reported to delay neutrophilapoptosis.[36][37][38] Thus, some bacteria – and those that are predominantly intracellular pathogens – can extend 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 asStreptococcus pyogenes are capable of altering neutrophil fate after phagocytosis by promoting rapid cell lysis and/or accelerating apoptosis to the point of secondary necrosis.[39][40]
Neutrophils also release an assortment of proteins in three types of granules by a process calleddegranulation. The contents of these granules have antimicrobial properties, and help combat infection.Glitter cells arepolymorphonuclear leukocyte neutrophils with granules.[41] Degranulation is postulated to occur in a hierarchical manner, with the sequential release of secretory vesicles, tertiary granules, specific granules, and azurophilic granules in response to increasing intracellular calcium concentrations.[42] The release of neutrophils by degranulation occurs throughexocytosis, regulated by exocytotic machinery including SNARE proteins,RAC2,RAB27, and others.[citation needed]
| Granule type | Protein |
|---|---|
| Azurophilic granules (or "primary granules") | Myeloperoxidase,bactericidal/permeability-increasing protein (BPI),defensins, and theserine proteasesneutrophil elastase,Proteinase 3 andcathepsin G |
| Specific granules (or "secondary granules") | Alkaline phosphatase,lysozyme,NADPH oxidase,collagenase,lactoferrin,histaminase,[43] andcathelicidin |
| Tertiary granules | Cathepsin,gelatinase, andcollagenase |
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.[44] Theseneutrophil extracellular traps (NETs) comprise a web of fibers composed ofchromatin andserine proteases[45] 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 a particularly important role for NETs insepsis, where NETs are formed within blood vessels.[46] Finally, NET formation has been demonstrated to augment macrophage bactericidal activity during infection.[47][48] Recently, NETs have been shown to play a role in inflammatory diseases, as NETs could be detected inpreeclampsia, a pregnancy-related inflammatory disorder in which neutrophils are known to be activated.[49] Neutrophil NET formation may also impactcardiovascular disease, as NETs may influencethrombus formation incoronary arteries.[50][51]NETs are now known to exhibit pro-thrombotic effects bothin vitro[52] andin vivo.[53][54] More recently, in 2020 NETs were implicated in the formation of blood clots in cases of severeCOVID-19.[55]
TANs can exhibit an elevated extracellular acidification rate when there is an increase in glycolysis levels.[56] 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 the phagocytosis of tumor cells. Utilizing a mouse model, they[who?] identified that both Glut1 and glucose metabolism increased in TANs found within a mouse who possessed lung adenocarcinoma.[56] A study showed that lung tumor cells can remotely initiate osteoblasts and these osteoblasts can worsen tumors in two ways. First, they can induce SiglecFhigh-expressing neutrophil formation that in turn promotes lung tumor growth and progression. Second, the osteoblasts can promote bone growth thus forming a favorable environment for tumor cells to grow to form bone metastasis.[57]
Low neutrophil counts are termedneutropenia. This can becongenital (developed at or before birth) or it can develop later, as in the case ofaplastic anemia or some kinds ofleukemia. It can also be aside-effect ofmedication, most prominentlychemotherapy. Neutropenia makes an individual highly susceptible to infections. It can also be the result of colonization by intracellular neutrophilic parasites.[citation needed]
Inalpha 1-antitrypsin deficiency, the importantneutrophil elastase is not adequately inhibited byalpha 1-antitrypsin, leading to excessive tissue damage in the presence of inflammation – the most prominent one beingemphysema. Negative effects of elastase have also been shown in cases when the neutrophils are excessively activated (in otherwise healthy individuals) and release the enzyme in extracellular space. Unregulated activity of neutrophil elastase can lead to disruption of pulmonary barrier showing symptoms corresponding withacute lung injury.[58] The enzyme also influences activity of macrophages by cleaving theirtoll-like receptors (TLRs) and downregulatingcytokine expression by inhibiting nuclear translocation ofNF-κB.[59]
InFamilial Mediterranean fever (FMF), a mutation in thepyrin (ormarenostrin) gene, which is expressed mainly in neutrophil granulocytes, leads to a constitutively activeacute-phase response and causes attacks offever,arthralgia,peritonitis, and – eventually –amyloidosis.[60]
Hyperglycemia can lead to neutrophil dysfunction. Dysfunction in the neutrophil biochemical pathwaymyeloperoxidase as well as reduced degranulation are associated with hyperglycemia.[61]
TheAbsolute neutrophil count (ANC) 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 / mm3 is considered neutropenia, but <500 cells / mm3 is considered severe.[62] There is also new research tying ANC tomyocardial infarction as an aid in early diagnosis.[63][64] Neutrophils promote ventricular tachycardia in acute myocardial infarction.[65]
Inautopsy, the presence of neutrophils in the heart or brain is one of the first signs of infarction, and is useful in the timing anddiagnosis of myocardial infarction andstroke.[citation needed]
![Neutrophils are seen in a myocardial infarction at approximately 12–24 hours,[66] as seen in this micrograph.](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aHistopathology_of_neutrophil_infiltration_in_myocardial_infarction.jpg)
![In stroke, they are beginning to infiltrate the infarcted brain after 6 to 8 hours.[67]](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aHistopathology_of_thalamus_infarction_at_approximately_24_hours%2c_high_magnification%2c_annotated.jpg)
Just like phagocytes, pathogens may evade or infect neutrophils.[68] 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.[68]
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 the low affinity Fc-γ receptor IIIb (FCGR3B :CD16b) The single known HNA-2a antigen is located onCD177. 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 β2integrin. HNA-4 is located on the αM chain (CD11b) and HNA-5 is located on the αL integrin unit (CD11a).[70]
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 the substrate, whereas cells of another subpopulation (neutrophil-cagers) produce reactive oxygen species less intensively, don't adhere to substrate and preserve their activity.[71][72][73][74][75] Additional studies have shown that lung tumors can be infiltrated by various populations of neutrophils.[76]
Neutrophils display highly directional amoeboid motility in infected footpad and phalanges. Intravital imaging was performed in the footpad path of LysM-eGFP mice 20 minutes after infection withListeria monocytogenes.[77]
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These data suggest that the function and not the number of phagocytes was altered by ingestion of sugars. This implicates glucose and other simple carbohydrates in the control of phagocytosis and shows that the effects last for at least 5 hr. On the other hand, a fast of 36 or 60 hr significantly increased (P < 0.001) the phagocytic index
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