Chemotaxis 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 the path of their migration. Neutrophils have a variety of specific receptors, including ones for the
complement system, 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 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 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.
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 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 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).
Phagocytosis of a neutrophil (yellow) phagocytosing
anthrax bacilli (orange). Scale bar is 5 μm.|alt= 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. Neutrophils are
phagocytes, capable of ingesting microorganisms or particles. For targets to be recognized, they must be coated in
opsoninsa process known as
antibody opsonization. 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 bacteriaand those that are predominantly intracellular pathogenscan 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.
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. 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. The release of neutrophils by degranulation occurs through
exocytosis, regulated by exocytotic machinery including SNARE proteins,
RAC2,
RAB27, and others.
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. These
neutrophil extracellular traps (NETs) comprise a web of fibers composed of
chromatin and
serine proteases that trap and kill extracellular microbes; thus, by forming NETs (NETosis), neutrophils can bind, disarm, and kill microbes independent of phagocytic uptake. These functions are achieved through the release of highly concentrated antimicrobial components including proteins from granules and powerful histone proteins from the nucleus. 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 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 the formation of blood clots in cases of severe
COVID-19.
Tumor-associated neutrophils (TANs) Tumor-associated neutrophils (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 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. ==Clinical significance==