Neutrophils, also recognised as neutrocytes, are the most abundant typeof white blood cell in circulation within mammals, usually consisting between40% and 70% of entire leukocyte concentration within our bloodstream. They aremultinucleated granulocytes with a distinctive phenotype with a nucleusconsisting of 3-5 lobes connected with chromatin. Neutrophils originate fromthe pluripotent, haematopoietic stem cells within bone marrow and endure a veryshort life span, typically only five to six days. They are criticalin fighting and controlling both fungal and bacterial infection due totheir ability to migrate to the site of infection from the peripheral bloodcirculation when tissue damage and invasion of a pathogen occurs.
Neutrophilsare highly specialised killing cells1 and are the most important cellinvolved in the acute phase of inflammatory response with their phagocyticnature allowing them to quickly recognise and engulf harmful invading pathogensremoving the infection.2They have the ability to eliminatepathogens through different mechanisms, one of these being the generation ofNeutrophil extracellular traps (NETs). These pathogens are then cleared byproteolytic enzymes, antimicrobial peptides and reactive oxygen species(ROS). Neutrophilsalso play a critical role in the regulation and pathogenesis of both acute andchronic inflammatory disease. There are three ways in which Neutrophils can be destroyed.
Apoptosis,Necrosis and NETosis.3Apoptosis, a normal phenomenon with isa frequently occurring form of cell death sometime referred to as programmedcell death. During apoptosis cells activate an intracellular death and commitsuicide. A type of proteolytic enzyme called caspases cleave specific proteinswithin the cell’s cytoplasm and nucleus, inducing the cell’s death. Apoptosisis a more favourable form of cell death as it causes less damage to surroundingcells. Remaining apoptotic bodies are phagocytosed with cellular organellesstill in-tact.
Necrosis is an un-programmed, unregulated, turbulent formof cell death in which enzymatic digestion takes place. Necrosis is causedby unpredicted external factors such as infection or trauma. Due to theruptured cellular membrane allowing the unregulated release ofoxidant-generating and proteolytic enzymes from the necrotic cell bodies,adjacent swelling frequently occurs as well as causing irreversible damage tosurrounding cells and tissue. NETosis is another form of programmed cell deaththat is accompanied by the formation of NETs.4 NETosis is distinct fromapoptosis and necrosis.
There are two types, suicidal NETosis and vitalNETosis. 5 NETosis can be characterized bydisintegration of nuclear and granular membranes, the decondensing of chromatinand the diffusion into extracellular space following the collapse of thenuclear membrane History of NETsNeutrophils, since their discovery have always been recognised to becrucial in the first line of defence when there is injury or infection. Howeverit was not until 1996 that the first discovery related to NETs occurred. Thediscovery, made by Takei et al9 whilst he was investigating the relationshipneutrophil activation and neutrophil death using a stimulant(phorbol-12-myristate-13-acetate or PMA ). The distinctive changes in theneutrophils morphology spiked his interest such as the fusion of the multi-lobednucleus followed by the decondensing of the chromatin from its typical compactstructure. The nuclear envelope then fragmented while the organelles remainedfunctioning. Following further observation he could see that the extracellularmembrane became ruptured in a ROS dependent mechanism.
In this case, the PMAreacted directly with protein kinase C producing ROS. This led him to theconclusion that there was an alternative pathway cell death independent fromApoptosis and Necrosis. It was not until 2004 this discovery was furtherinvestigated and coined NETosis by V.Brinkmann8 and his colleagues. Brinkmann et al.
declared that neutrophils, following PMA stimulationwill extrude DNA forming an extracellular web like structure. He discovered thatthis web like structure was decorated in bactericidal proteins which were oncecontained in intracytoplasmic granules. 10 The mechanism used by NETs wasunique from the simple engulfment of pathogens and release of antimicrobialsand instead binds together microorganisms preventing spreading and furtherinfection introduced a new host defence structure. Suicidal NETosis Vs vital NETosisNETosis is initiated by certain in stimuli. In the case of suicidalNETosis, it is initiated by the binding of ligands to both neutrophil toll likereceptors (TLRs) and the receptors for IgG-FC, complement and cytokines.