Regulated Cell Death

In this chapter, the various subroutines of regulated cell death are neatly described by highlighting apoptosis and subforms of regulated necrosis such as necroptosis, ferroptosis, pyroptosis, and NETosis. Typically, all forms of regulated necrosis are defined by finite rupture of the plasma cell membrane. Apoptosis is characterized by an enzymatic machinery that consists of caspases which cause the morphologic features of this type of cell death. Mechanistically, apoptosis can be instigated by two major cellular signalling pathways: an intrinsic pathway that is initiated inside cells by mitochondrial release of pro-apoptotic factors or an extrinsic pathway that is initiated at the cell surface by various death receptors. In necroptosis, the biochemical processes are distinct from those found in apoptosis; in particular, there is no caspase activation. As such, necroptosis is a kinase-mediated cell death that relies on “receptor-interacting protein kinase 3” which mediates phosphorylation of the pseudokinase “mixed lineage kinase domain-like protein.” While ferroptosis is an iron-dependent, oxidative form of regulated necrosis that is biochemically characterized by accumulation of ROS from iron metabolism, oxidase activity, and lipid peroxidation products, pyroptosis is defined as a form of cell death (predominantly of phagocytes) that develops during inflammasome activation and is executed by caspase-mediated cleavage of the pore-forming protein gasdermin D. Finally, NETosis refers to a regulated death of neutrophils that is characterized by the release of chromatin-derived weblike structures released into the extracellular space. The chapter ends up with a discussion on the characteristic feature of regulated necrosis: the passive release of large amounts of constitutive DAMPs as a consequence of final plasma membrane rupture as well as the active secretion of inducible DAMPs earlier during the dying process. Notably, per cell death subroutine, the active secretion of inducible DAMPs varies, thereby determining different immunogenicity of dying cells.