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).