Other forms of programmed necrosis
Necroptosis is the best characterized form of programmed necrosis, but
is not the only one. In general, all modes of regulated necrosis exhibit
typical hallmarks like cellular rounding and swelling (known as
oncosis), granulation at cytoplasmic level and plasma membrane rupture,
however physiological and biochemical differences lead to a variety of
sub-classes with particular mechanisms (reviewed in
(Vanden Berghe et al., 2015)). These
non-apoptotic cell death modalities include the mitochondrial
permeability transition-mediated regulated necrosis (MPT-mediated
necrosis), parthanatos and ferroptosis. The first one, is induced by a
mitochondrial pore composed of at least Cyclophilin D (CYPD) (the only
component of the pore that has been identified so far), whereas
parthanatosis caused by an excessive PARylation of intracellular
proteins by Poly-ADP ribose polymerase 1 (PARP1) provoking a depletion
of NAD+ and ATP that leads to necrotic cell death
(Galluzzi et al., 2018;
Pasparakis & Vandenabeele, 2015;
Vanden Berghe et al., 2015). On the other
hand, ferroptosis involves an iron-dependent oxidative stress that is
produced by a decrease in cysteine uptake (the oxidized form of
cysteine), a deficit of GSH (reduced glutathione) and a depletion of the
enzyme glutathione peroxidase 4 (GPX4)
(Dixon et al., 2012;
Pasparakis & Vandenabeele, 2015). In
neurons, it has been reported a form of ferroptosis called oxytosis,
which occurs as a result of glutamate toxicity by the blockade of the
antiporter system Xc-producing the
deficit of cystine and the iron-dependent production of reactive oxygen
species (Albrecht et al., 2010;
Tan, Schubert, & Maher, 2001).
In addition, pyroptosis, pyronecrosis and regulated necrosis associated
with the release of extracellular traps (termed as ETosis) are
proinflammatory and microbial-induced forms of programmed necrosis which
occur in specialized immune cells
(Galluzzi et al., 2018;
Vanden Berghe et al., 2015). Pyroptosis
is triggered by canonical or non-canonical inflammasome stimulation,
which induces activation of Caspase 1 or Caspase 11, respectively, while
pyronecrosis has been described as a Caspase 1/Caspase 11-independent
cell death that involves Cathepsin B release and lysosomal
permeabilization (D’Arcy, 2019;
Kepp, Galluzzi, Zitvogel, & Kroemer,
2010; Miao et al., 2011). The mechanism
causing cell death has been better characterized in pyroptosis and is
based in osmotic imbalance and cellular swelling like occurs in
necroptosis, but the pore forming protein involved is Gasdermine D
(GSDMD) instead of MLKL. GSDMD is proteolithicaly activated by active
Caspase 1 upon inflammosome stimulation
(X. Liu et al., 2016).
ETosis, also known as NETosis (from Neutrophil Extracellular Traps),
occurs primary in neutrophils, but also in other innate immune cells,
and is characterized by the release of chromatin structures with
associated histones (called extracellular traps) that represents an
efficient antimicrobial mechanism (Allam et
al., 2014). The molecular events underlying this form of PCD have been
characterized and it has been demonstrated that NAPH oxidase 4 (NOX4), a
common enzyme in neutrophils, is a key component for the activation of
this pathway. The hyperactivation of this enzyme in response to
pathogens is mediated by the extracellular signal-regulated kinase
(ERK), changing the ROS balance within the neutrophil and inducing
Myeloperoxidase (MPO) and Neutrophil elastase (NE) activity, a
downstream event that leads to chromatin condensation and massive
permeabilization (including nucleus, granules and plasma membrane),
interestingly through the pore forming protein GSDMD, a common feature
with pyroptosis. It has been described that NE is implicated in GSDMD
processing and activation, as well as histone cleavage, a modification
that together with histone citrullination (mediated by peptidylarginine
deiminase 4 or PAD4), facilitate DNA and chromatin rearrange. The final
consequence is the extrusion of the extracellular trap with histones,
proteases and granular proteins, resulting in the death of the
neutrophil. Under certain conditions, the extrusion can occurs with
neutrophil survival, a process termed as “vital NETosis”.
(Burgener & Schroder, 2020).