Chapter one - Programmed Necrosis: From Molecules to Health and Disease
Introduction
One of the first attempts to classify cell death was undertaken in the early 1970s by Schweichel and Merker (1973). These authors analyzed the response of rat embryos to toxicants and proposed that cells can undergo type I cell death associated with heterophagy, type II cell death associated with autophagy, and type III cell death without digestion (Schweichel and Merker, 1973). This came only 1 year after the seminal paper by Kerr et al. (1972), in which they described for the first time a peculiar type of cell death that is characterized by cell shrinkage and named it apoptosis, a Greek word meaning “falling off” of petals or leaves from plants or trees. Also owing to the work of Robert Horvitz on Caenorhabditis elegans, apoptosis (type I cell death in Schweichel's and Merker's classification) soon turned out to be a finely regulated process that is involved in a plethora of developmental and physiopathological settings (Lettre and Hengartner, 2006). The notion that autophagy (type II cell death) constitutes a bona fide cell death mechanism has recently been infirmed (Kroemer and Levine, 2008), exception made for a few specific developmental scenarios such as the involution of salivary glands in Drosophila melanogaster (Berry and Baehrecke, 2007). For long, necrosis (type III cell death) has been viewed as a purely accidental cell death modality and on these grounds has been opposed to apoptosis, the most prominent executor of programmed cell death.
At the end of the 1980s came the first hints that necrosis might also rely on genetically encoded mechanisms. Laster et al. (1988) indeed reported that, depending on the cell type, tumor necrosis factor (TNF) could induce either apoptosis (which they described as being characterized by nuclear disintegration and “boiling” cytoplasm) or necrosis (leading to a “balloon-like” plasma membrane in the absence of nuclear disintegration). Between 1992 and 1998, additional lines of evidence accumulated suggesting that necrosis can also be regulated. In particular, it was shown that mitochondrial reactive oxygen species (ROS) are required for the full-blown cytotoxic response to TNF in murine fibrosarcoma L929 cells (Goossens et al., 1995, Schulze-Osthoff et al., 1992), that the responsiveness of these cells to TNF depends on glutamine metabolism (Goossens et al., 1996), and importantly, that caspase inhibition can switch the lethal response to TNF from apoptosis to necrosis (Hirsch et al., 1997, Vercammen et al., 1998a). A couple of years later, in 2000, a landmark paper reported that, in some cell types, the death receptor FAS can trigger nonapoptotic cell death that is independent of caspases but dependent on both the adaptor protein FAS-associated protein with a death domain (FADD) and on the presence and enzymatic activity of the receptor-interacting serine-threonine kinase 1 (RIPK1, a.k.a. RIP1; Holler et al., 2000). In the following decade, the consensus on the notion of programmed necrosis kept on growing and several papers explicitly referring to necrosis as a regulated mechanisms were published (Chan et al., 2003, Zong et al., 2004). In 2005, Junying Yuan's laboratory reported the discovery of necrostatin-1, a specific and potent small-molecule inhibitor of TNF-elicited regulated necrosis, which they dubbed necroptosis (Degterev et al., 2005). Only in 2008, however, the molecular target of necrostatin-1 was identified, and it turned out to be RIP1 (Degterev et al., 2008). In the same year, a large system biology study of necroptosis was published reporting the discovery of a set of 432 necroptosis regulators (Hitomi et al., 2008). The most recent significant advances in necroptosis research, however, date back to 2009, when three distinct research groups deciphered the necroptotic role of the RIP1-related kinase RIP3 (Cho et al., 2009, He et al., 2009, Zhang et al., 2009; see below).
Similar to the notion that necrosis can constitute a regulated cell death mechanism, the morphotype of necrotic cells has long been disregarded. In 1972, Kerr and colleagues first introduced the term “apoptosis” to describe a cell death subroutine with specific morphological characters (Kerr et al., 1972). These include the retraction of pseudopodes, the rounding up of cells and the detachment from the basal membrane or cell culture substrate, a consistent decrease in cellular volume (pyknosis), chromatin condensation and nuclear fragmentation (karyorrhexis), the blebbing of the plasma membrane, the shedding of vacuoles containing parts of the cytoplasm and apparently intact organelles (the so-called apoptotic bodies), and the in vivo uptake of apoptotic corpses by neighboring cells or professional phagocytes (Galluzzi et al., 2007).
In contrast to the detailed morphological characterization of apoptosis, dying cells were initially classified as necrotic in a negative fashion, that is, when they exhibited neither an apoptotic morphotype nor an extensive vacuolization of the cytoplasm (which was used as an indicator of autophagic cell death). The interest in the morphotype of necrotic cells grew along with the discovery that necrosis can be under molecular control. Now, it is accepted that necrotic cells also share peculiar morphological traits such as an increasingly translucent cytoplasm, the osmotic swelling of organelles, minor ultrastructural modifications of the nucleus (in particular, the dilatation of the nuclear membrane and the condensation of chromatin into small patches) and an increased cell volume (oncosis), which culminate in the breakdown of the plasma membrane (Kroemer et al., 2009). Moreover, necrotic cells do not fragment into discrete corpses as their apoptotic counterparts do, nor do so their nuclei, which indeed have been reported to accumulate in necrotic tissues.
In the absence of a phagocytic system, necrosis represents the endpoint of all cell death subroutines (Galluzzi et al., 2009a). Thus, the plasma membrane of apoptotic bodies that are not cleared by professional phagocytes progressively loses its integrity, leading to the spillage of their content into the extracellular microenvironment. This postmortem process is called secondary necrosis and reflects the gradual degradation that all kinds of biological material undergo with time (if not handled by specific clearing systems). On the contrary, primary necrosis (be it regulated or not) constitutes a bona fide cell death mechanism. This review will focus on the molecular mechanisms and pathophysiological implications of necroptosis and of other forms of programmed necrosis.
Section snippets
Death receptor paradigm
Probably the most extensively investigated model of necroptosis is that elicited by the ligation of tumor necrosis factor receptor 1 (TNFR1) (Fig. 1.1). Nevertheless, TNFR1 does not constitute the sole pronecroptotic receptor described to date. Thus, other death receptors including CD95 (a.k.a. FAS; Holler et al., 2000), TNFR2 (Chan et al., 2003), and the TNF-related apoptosis-inducing ligand receptors 1 and 2 (TRAILR1 and TRAILR2; Laster et al., 1988, Vercammen et al., 1998b) reportedly induce
Execution of Necroptosis
After the discovery of the RIP1–RIP3 interaction, major efforts have been undertaken to understand how the necrosome activates necrotic cell death. However, since this field of research is very young, only a few insights into the molecular mechanisms that underlie the execution of necroptosis have been obtained to date. Some additional mechanistic hints derive from studies that have been performed when necrosis was still viewed as an accidental cell death mode only. For instance, highly
Programmed Necrosis in Model Organisms
Many efforts have been devoted to the exploration of apoptosis in nonmammalian animal models, fungi (in particular yeast), and protists. Recent evidence indicates that necroptosis also occurs in different phyla, revealing evolutionarily conserved mechanisms of nonapoptotic cell death execution (Fig. 1.3; Table 1.1).
Necroptosis in Health and Disease
The first scientific reports pointing to a physiological role for necrosis have been published at the end of the twentieth century (Barkla and Gibson, 1999, Roach and Clarke, 2000). Thus, Barkla et al. and Roach et al. showed that (regulated forms of) necrosis can occur during mammalian development, in particular at the bone growth plate (i.e., the zone of the bone that controls its length) (Roach and Clarke, 2000), as well as in adult tissue homeostasis, for instance, in the lower regions of
Concluding Remarks
During the past decade, the perception of necrosis as a merely accidental cell death modality has been definitively abandoned. Evidence from dozens of laboratories worldwide has accumulated to unequivocally demonstrate that necrosis, similar to apoptosis, can be a highly regulated process with important pathophysiological and therapeutic implications. Although the field of necroptosis research is still in its infancy, some mechanist insights into the molecular machinery that control and execute
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