Neutrophil

This article is about neutrophils, cells of the immune system. For organisms that grow in neutral pH environments see: Neutrophile.

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A neutrophil granulocyte from a blood sample squeezed from a slightly-infected cut, and stained with Wright's stain.  This image was produced from nine separate photographs, taken with a cheap digital camera through a 60X dry objective and a 10X eyepiece; and stacked using AstroStack software to produce one image of increased clarity and resolution.

A blood smear showing a neutrophil granulocyte; the three-lobulated nucleus can be seen. This picture has been stained with MayGrunwald Giemsa, and observed with a 100x objective in oil immersion.

Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They form part of the polymorphonuclear cell family (PMNs) together with basophils and eosinophils. (For an overview of neutrophils and their function, see recent reviews by Carl Nathan and Witko-Sarsat et al. Also see Klebanoff & Clark.)

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.

Neutrophils are normally found in the blood stream. However, during the beginning (acute) phase of inflammation, particularly as a result of bacterial infection and some cancers, neutrophils are one of first-responders of inflammatory cells to migrate toward the site of inflammation, firstly through the blood vessels, then through interstitial tissue, following chemical signals (such as Interleukin-8 (IL-8), Interferon-gamma (IFN-gamma), and C5a) 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 the hallmark of acute inflammation.

Measurement of neutrophils

Neutrophil granulocyte migrates from the blood vessel to the matrix, sensing proteolytic enzymes, in order to determine intercellular connections (to the improvement of its mobility) and envelop bacteria through phagocytosis.

Neutrophil granulocytes have an average diameter of 12-15 micrometers (µm) in peripheral blood smears.

With the eosinophil and the basophil, they form the class of polymorphonuclear cells, named for the nucleus's characteristic multilobulated shape (as compared to lymphocytes and monocytes, the other types of white cells). Neutrophils are the most abundant white blood cells in humans (approximately 10^11 are produced daily) ; they account for approximately 70% of all white blood cells (leukocytes).

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

The stated normal range for human blood counts varies between laboratories, but a neutrophil count of 2.5-7.5 x 10⁹/L is 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.

Lifespan

The average half-life of non-activated neutrophils in the circulation is about 12 hours. Upon activation, they marginate (position themselves adjacent to 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 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, 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.

Chemotaxis

Neutrophils undergo a process called chemotaxis, 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-gamma), and C5a, which these cells use to direct the path of their migration.

Anti-Microbial Function

Neutrophil

Being highly motile, neutrophils quickly congregate at 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 defence against invading pathogens. Neutrophils have three strategies for directly attacking micro-organisms: phagocytosis (ingestion), release of soluble anti-microbials (including granule proteins) and generation of neutrophil extracellular traps (NETs) .

Phagocytosis

Neutrophils are phagocytes, capable of ingesting microorganisms or particles. They can internalize and kill many 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 dismutates, spontaneously or through catalysis via enzymes known as superoxide dismutases (Cu/ZnSOD and MnSOD), to hydrogen peroxide, which is then converted to hypochlorous acid (HOCl, also known as chlorine bleach) by the green heme enzyme myeloperoxidase. It is thought that the bactericidal properties of HOCl are enough to kill bacteria phagocytosed by the neutrophil, but this may instead be step necessary for the activation of proteases.

Degranulation

Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation:

Granule type	Protein
specific granules (or "secondary granules")	Lactoferrin and Cathelicidin
azurophilic granules (or "primary granules")	myeloperoxidase, bactericidal/permeability increasing protein (BPI), Defensins and the serine proteases neutrophil elastase and cathepsin G
tertiary granules	cathepsin and gelatinase

NETs

Zychlinsky and colleagues recently described a new striking observation that activation of neutrophils causes the release of web-like structures of DNA; this represents a third mechanisms for killing bacteria. These neutrophil extracellular traps (NETs) comprise a web of fibers composed of chromatin and serine proteases that trap and kill microbes extracellularly. 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 partcularly important role for NETs in sepsis, where NET are formed within blood vessels. 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.

Role in disease

Low neutrophil counts are termed neutropenia. This can be congenital (genetic disorder) 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. Neutropenia can be the result of colonization by intracellular neutrophilic parasites.

Functional disorders of neutrophils are often hereditary. They are disorders of phagocytosis or deficiencies in the respiratory burst (as in chronic granulomatous disease, a rare immune deficiency, and myeloperoxidase deficiency).

In alpha 1-antitrypsin deficiency, the important neutrophil enzyme elastase is not adequately inhibited by alpha 1-antitrypsin, leading to excessive tissue damage in the presence of inflammation - most prominently pulmonary emphysema.

In Familial Mediterranean fever (FMF), 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.

Media

• A rapidly moving neutrophil can be seen taking up several conidia over an imaging time of 2 h with one frame every 30 s
• A neutrophil can be seen here selectively taking up several Candida yeasts (fluorescently labeled in green) despite several contacts with Aspergillus fumigatus conidia (unlabeled, white/clear) in a 3-D collagen matrix. Imaging time was 2 h with an interval of 30 s after every frame

[1] Neutrophils display highly directional amoeboid motility in infected footpad and phalanges. Intravital imaging was performed in the footpad path of LysM-eGFP mice 20 min after infection with LM. Public Library of Science

Additional images

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  A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange)
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  Blood cell lineage
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  More complete lineages (very large)