Neutrophil

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Neutrophil
platelets. Intra-cellular granules are visible in the cytoplasm (Giemsa stained).
Details
SystemImmune system
FunctionPhagocytosis
Identifiers
MeSHD009504
THH2.00.04.1.02012
FMA62860
Anatomical terms of microanatomy]

Neutrophils (also known as neutrocytes, heterophils or polymorphonuclear leukocytes) 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.[1] They form an essential part of the innate immune system, with their functions varying in different animals.[2]

They are formed from

polymorphonuclear cells family (PMNs) together with basophils and eosinophils.[3][4][5]

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 a nucleus divided into 2–5 lobes.[6]

Neutrophils are a type of

fMLP, leukotriene B4, and hydrogen peroxide (H2O2)[10] in a process called chemotaxis. They are the predominant cells in pus, 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;

pathogens
being indigestible, they might not be able to resolve certain infections without the assistance of other types of immune cells.

Structure

Neutrophil granulocyte migrates from the blood vessel to the matrix, secreting proteolytic enzymes to dissolve intercellular connections (to the improvement of its mobility) and envelop bacteria through phagocytosis.
Hypersegmented neutrophil

When adhered to a surface, neutrophil granulocytes have an average diameter of 12–15 

peripheral blood smears. In suspension, human neutrophils have an average diameter of 8.85 µm.[13]

With the

mitochondria and ribosomes are sparse, and the rough endoplasmic reticulum is absent.[14]: 170  The cytoplasm also contains about 200 granules, of which a third are azurophilic.[14]
: 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 notably

vitamin 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.

Reference ranges for blood tests of white blood cells, comparing neutrophil amount (shown in pink) with that of other cells

Neutrophils are the most abundant white blood cells in humans (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 of African and Middle Eastern descent may have lower counts, which are still normal.[16] 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

pseudopods as they hunt for antigens.[17]

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.[18] 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.[19][20]

Development

Life span

The average lifespan of inactivated human neutrophils in the circulation has been reported by different approaches to be between 5 and 135 hours.[21][22]

Upon activation, they marginate (position themselves adjacent to the blood vessel endothelium) and undergo

splenic reserve following myocardial infarction.[24]

Neutrophils are much more numerous than the longer-lived

parasitize phagocytes (e.g. Leishmania[25]) because 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.[23]

Neutrophils will be removed after

on the cell surface are involved in this process.

Function

Chemotaxis

Neutrophils undergo a process called

interleukin-8 (IL-8), interferon gamma (IFN-γ), C3a, C5a, and leukotriene B4
, which these cells use to direct 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.[26]

In leukocytes responding to a

plasma 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.

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.[28]

Anti-microbial function

Being highly motile, neutrophils quickly congregate at a focus of infection, attracted by cytokines expressed by activated endothelium, mast cells, and macrophages. Neutrophils express[29] 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. Neutrophils have three methods for directly attacking micro-organisms: phagocytosis (ingestion), degranulation (release of soluble anti-microbials), and generation of neutrophil extracellular traps (NETs).[30]

Phagocytosis

Long rod-shaped bacteria, one of which has been partially engulfed by a larger blob-shaped white blood cell. The shape of the cell is distorted by undigested bacterium inside it.
Scanning electron micrograph of a neutrophil (yellow) phagocytosing anthrax bacilli (orange). Scale bar is 5 μm.

Neutrophils are

microbes, each phagocytic event resulting in 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, 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 a step necessary for the activation of proteases.[31]

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.[32][33][34] 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 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.[35][36]

Degranulation

Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation. The contents of these granules have antimicrobial properties, and help combat infection. Glitter cells are polymorphonuclear leukocyte neutrophils with granules.[37]

Granule type Protein
Azurophilic
granules (or "primary granules")
bactericidal/permeability-increasing protein (BPI), defensins, and the serine proteases neutrophil elastase, Proteinase 3 and cathepsin G
Specific granules (or "secondary granules")
cathelicidin
Tertiary granules Cathepsin, gelatinase, and collagenase

Neutrophil extracellular traps

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.

preeclampsia, a pregnancy-related inflammatory disorder in which neutrophils are known to be activated.[44] Neutrophil NET formation may also impact cardiovascular disease, as NETs may influence thrombus formation in coronary arteries.[45][46]
NETs are now known to exhibit pro-thrombotic effects both in vitro[47] and in vivo.[48][49] More recently, in 2020 NETs were implicated in the formation of blood clots in cases of severe COVID-19.[50]

Tumor Associated Neutrophils

TANs can exhibit an elevated extracellular acidification rate when there is an increase in glycolysis levels.[51] 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 identified that both Glut1 and glucose metabolism increased in TANs found within a mouse who possessed lung adenocarcinoma.[51]

Clinical significance

Micrograph showing several neutrophils during an acute inflammation

Low neutrophil counts are termed

side-effect of medication, most prominently chemotherapy
. Neutropenia makes an individual highly susceptible to infections. It can also be the result of colonization by intracellular neutrophilic parasites.

In

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 the enzyme in extracellular space. Unregulated activity of neutrophil elastase can lead to disruption of pulmonary barrier showing symptoms corresponding with acute lung injury.[52] 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.[53]

In

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.[54]

Hyperglycemia can lead to neutrophil dysfunction. Dysfunction in the neutrophil biochemical pathway myeloperoxidase as well as reduced degranulation are associated with hyperglycemia.[55]

The Absolute 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.[56] There is also new research tying ANC to myocardial infarction as an aid in early diagnosis.[57][58] Neutrophils promote ventricular tachycardia in acute myocardial infarction.[59]

In autopsy, 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.

Pathogen evasion and resistance

Just like phagocytes, pathogens may evade or infect neutrophils.[62] 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.[62]

Neutrophils can also serve as host cell for various parasites that infects them avoding phagocytosis, including:

Neutrophil antigens

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 :

CD11a).[65]

Subpopulations

Activity of neutrophil-killer and neutrophil-cager in NBT test[66]

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.[66][67][68][69][70] Additional studies have shown that lung tumors can be infiltrated by various populations of neutrophils.[71]

Video

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 with Listeria monocytogenes.[72]

Additional images

  • Blood cell lineage
    Blood cell lineage
  • More complete lineages
    More complete lineages

See also

References

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External links