Neutrophils, and nucleus, inducing the cell’s death.

Neutrophils, also recognised as neutrocytes, are the most abundant type
of white blood cell in circulation within mammals, usually consisting between
40% and 70% of entire leukocyte concentration within our bloodstream. They are
multinucleated granulocytes with a distinctive phenotype with a nucleus
consisting of 3-5 lobes connected with chromatin. Neutrophils originate from
the pluripotent, haematopoietic stem cells within bone marrow and endure a very
short life span, typically only five to six days. They are critical
in fighting and controlling both fungal and bacterial infection due to
their ability to migrate to the site of infection from the peripheral blood
circulation when tissue damage and invasion of a pathogen occurs. Neutrophils
are highly specialised killing cells1 and are the most important cell
involved in the acute phase of inflammatory response with their phagocytic
nature allowing them to quickly recognise and engulf harmful invading pathogens
removing the infection.
2They have the ability to eliminate
pathogens through different mechanisms, one of these being the generation of
Neutrophil extracellular traps (NETs). These pathogens are then cleared by
proteolytic enzymes, antimicrobial peptides and reactive oxygen species
(ROS).   Neutrophils
also play a critical role in the regulation and pathogenesis of both acute and
chronic inflammatory disease.  

 

There are three ways in which Neutrophils can be destroyed. Apoptosis,
Necrosis and NETosis.
3Apoptosis, a normal phenomenon with is
a frequently occurring form of cell death sometime referred to as programmed
cell death. During apoptosis cells activate an intracellular death and commit
suicide. A type of proteolytic enzyme called caspases cleave specific proteins
within the cell’s cytoplasm and nucleus, inducing the cell’s death. Apoptosis
is a more favourable form of cell death as it causes less damage to surrounding
cells. Remaining apoptotic bodies are phagocytosed with cellular organelles
still in-tact. Necrosis is an un-programmed, unregulated, turbulent form
of cell death in which enzymatic digestion takes place. Necrosis is caused
by unpredicted external factors such as infection or trauma. Due to the
ruptured cellular membrane allowing the unregulated release of
oxidant-generating and proteolytic enzymes from the necrotic cell bodies,
adjacent swelling frequently occurs as well as causing irreversible damage to
surrounding cells and tissue. NETosis is another form of programmed cell death
that is accompanied by the formation of NETs.4  NETosis is distinct from
apoptosis and necrosis. There are two types, suicidal NETosis and vital
NETosis. 5 NETosis can be characterized by
disintegration of nuclear and granular membranes, the decondensing of chromatin
and the diffusion into extracellular space following the collapse of the
nuclear membrane

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History of NETs

Neutrophils, since their discovery have always been recognised to be
crucial in the first line of defence when there is injury or infection. However
it was not until 1996 that the first discovery related to NETs occurred. The
discovery, made by Takei et al9 whilst he was investigating the relationship
neutrophil activation and neutrophil death using a stimulant
(phorbol-12-myristate-13-acetate or PMA ). The distinctive changes in the
neutrophils morphology spiked his interest such as the fusion of the multi-lobed
nucleus followed by the decondensing of the chromatin from its typical compact
structure. The nuclear envelope then fragmented while the organelles remained
functioning. Following further observation he could see that the extracellular
membrane became ruptured in a ROS dependent mechanism. In this case, the PMA
reacted directly with protein kinase C producing ROS. This led him to the
conclusion that there was an alternative pathway cell death independent from
Apoptosis and Necrosis. It was not until 2004 this discovery was further
investigated and coined NETosis by V.Brinkmann8 and his colleagues.
 Brinkmann et al. declared that neutrophils, following PMA stimulation
will extrude DNA forming an extracellular web like structure. He discovered that
this web like structure was decorated in bactericidal proteins which were once
contained in intracytoplasmic granules. 10 The mechanism used by NETs was
unique from the simple engulfment of pathogens and release of antimicrobials
and instead binds together microorganisms preventing spreading and further
infection introduced a new host defence structure.

 

Suicidal NETosis Vs vital NETosis

NETosis is initiated by certain in stimuli. In the case of suicidal
NETosis, it is initiated by the binding of ligands to both neutrophil toll like
receptors (TLRs) and the receptors for IgG-FC, complement and cytokines.