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Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of white blood cells in humans and form an essential part of the immune system. They form part of the polymorphonuclear cell family (PMN's) 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.
Their name arrives 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 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 react within an hour of tissue injury and are the hallmark of acute inflammation.
Measurement of neutrophils
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).
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.
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) is likely to first encounter is a neutrophil. Some experts feel that the short lifetime of neutrophils is an evolutionary adaptation to minimize 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. However, because neutrophil antimicrobial products can also damage host tissues, other authorities feel that their short life is an adaptation to limit damage to the host during inflammation.[How to reference and link to summary or text]
Neutrophils undergo a process called chemotaxis, which allows them to migrate toward sites of infection or inflammation. Cell surface receptors are able 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.
Neutrophils are phagocytes, capable of ingesting microorganisms or particles. They can internalise 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 has not been proven conclusively.
Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation:
|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, gelatinase|
Zychlinsky and colleagues recently described a new striking observation that activation of neutrophils causes the release of web-like structures of DNA, in addition to the more traditional mechanisms for killing bacteria, such as phagocytosis. 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 predisposes heavily for infection. 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 constitutionally active acute phase response and causes attacks of fever, arthralgia, peritonitis, and - eventually - amyloidosis.
Plasma - Hematopoietic stem cells
|Lymphoid - WBC|
|Myeloid - WBC||
Granulocytes (Neutrophil, Eosinophil, Basophil) - Mast cell precursors
|Myeloid - RBC||
Reticulocyte - Normoblast
Immune system / Immunology / Psychoneuroimmunology
|Systems||Adaptive immune system vs. Innate immune system • Humoral immune system vs. Cellular immune system • Complement system (Anaphylatoxins)|
|Antibodies and antigens||Antibody (Monoclonal antibodies, Polyclonal antibodies, Autoantibody) • Allotype • Isotype • Idiotype • Antigen (Superantigen)|
|Immune cells||White blood cells (T cell, B cell, NK cell, Mast cell, Basophil, Eosinophil) • Phagocyte (Neutrophil, Macrophage, Dendritic cell) • Antigen-presenting cell • Reticuloendothelial system|
|Immunity vs. tolerance||Immunity • Autoimmunity • Allergy • Tolerance (Central) • Immunodeficiency|
|Immunogenetics||Somatic hypermutation • V(D)J recombination • Immunoglobulin class switching • MHC / HLA|
|Other||Cytokines • Inflammation • Opsonin|
- Nathan, Carl (2006). Neutrophils and immunity: challenges and opportunities. Nature Reviews Immunology 6 (March): 173–82.
- Witko-Sarsat, V, Rieu P, Descamps-Latscha B, Lesavre P, Halbwachs-Mecarelli L (2000). Neutrophils: molecules, functions and pathophysiological aspects. Lab Invest 80 (5): 617–53.
- Klebanoff, SJ, Clark, RA (1978). The Neutrophil: Function and Clinical Disorders.
- Waugh, DJ (2008). The interleukin-8 pathway in cancer.. Clinical Cancer Research 14 (21): 6735–41.
- De Larco, JE (2004). The Potential Role of Neutrophils in Promoting the Metastatic Phenotype of Tumors Releasing Interleukin-8.. Clinical Cancer Research 10 (15): 4895–900.
- Cohen, Stephen. Burns, Richard C. Pathways of the Pulp, 8th Edition. St. Louis: Mosby, Inc. 2002. page 465.
- Brinkmann, Volker, Ulrike Reichard, Christian Goosmann, Beatrix Fauler, Yvonne Uhlemann, David S. Weiss, Yvette Weinrauch, Arturo Zychlinsky (2004-03-05). Neutrophil Extracellular Traps Kill Bacteria. Science 303 (5663): 1532–1535.
- Clark, SR, Ma AC, Tavener AS, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, DeVinney R, Doig CJ, Green FHY and Kubes P (2007). Platelet Toll-Like Receptor-4 Activates Neutrophil Extracellular Traps to Ensnare Bacteria in Endotoxemic and Septic Blood. Nature Medicine 13 ((4)): 463–9.
- Gupta, AK, Hasler P, Holzgreve W, Hahn S. (2007). Neutrophil NETs: a novel contributor to preeclampsia-associated placental hypoxia?. Semin Immunopathol 29 (2): 163–7.
- Ozen, S (2004). Familial mediterranean fever: revisiting an ancient disease.. European Journal of Pediatrics 162 (7-8): 449–54.
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