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CHaPTEr 13 Regulated Necrosis and Its Immunogenicity 203

express caspase-inhibitors, such as crmA (e.g., cowpox virus), in all metabolically active cells by ROS generated in mitochondria
whereas viral protein M45 (e.g., CMV) specifically targets and peroxisomes and at the plasma membrane. 2,14 Computed
necroptosis. M45 has been demonstrated to be a viral RHIM models of sepsis metabolomics also predict a benefit in improving
domain and thus suppresses DAI-induced RIPK3 oligomerization intracellular cysteine levels, but these results still await experi-
within the necrosome. Interestingly, cytomegalovirus (CMV) is mental verification.
a member of the herpesvirus family, which is famous for its GPX4 requires glutathione (GSH) to function. Inhibition of
−
persistence within the host. One might conclude that this virus the Glu/Cys-antiporter system X c in the plasma membrane
adapted to the necroptotic trapdoor by this mechanism. depletes intracellular cysteine required for GSH synthase. Inhibi-
−
During necroptosis, some chemokines (Chapter 10) and tors of antiporter system X c are inducers of ferroptosis, such as
cytokines (Chapter 9) are actively produced to be released apart the compound “erastin,” which was found in a screen for lethal
from DAMPs. These include CXCL1 and IL-33, a stimulator of compounds against Ras-transformed tumor cells. Inhibitors of
ST2 signaling on Tregs. This suggests that necroptosis, apart this process have also derived from screens, such as the first-in-
15
from being immunogenic through the release of DAMPs, also class compound ferrostatin-1. In fact, it is no wonder that
limits the inflammatory response to a certain surrounding of ferroptosis inhibitors have been identified in cancer cell lines,
the damage by creating a microenvironment that may prevent as evidence accumulates that many cancers are highly sensitive
necroptosis from causing a systemic inflammatory response to ferroptosis induction, especially lymphomas and clear cell
16
syndrome (SIRS) and death. Necroptosis may thus be the least renal cancer. Interestingly, p53, which is among the most mutated
immunogenic RN pathway (see Fig. 13.4). or deleted proteins in diverse cancers, is also an inhibitor of
−
system X c . Thus p53 may mediate some of its antitumor proper-
CLINICaL rELEVaNCE ties by inducing ferroptosis.
As GPX4 is responsible for efficient repair of oxidized sphin-
Selection of Clinically Relevant Conditions golipids, GPX4 inhibition by GSH depletion, direct allosteric
Associated With Necroptosis inhibitors (e.g., RSL3), or genetic depletion leads to accumulation

• Acute liver failure of peroxidized lipids. Defects in enzymes required for generation
• Autoimmune disorders of polyunsaturated fatty acids, such as acyl-CoA synthetase
• Acute respiratory distress syndrome (ARDS) long-chain family member 4 (ACSL4) or lysophosphatidylcholine
• Cancer (necrosis in the center of solid tumors) acyltransferase 3 (LPCAT3), sensitize cells to undergo ferroptosis
• Chemotherapy as well, further emphasizing the role of lipid peroxidation.
• Contrast-induced acute kidney injury (CIAKI) Interestingly, although known as a redox equivalent, NADPH
• Myocardial infarction depletion has been identified as a downstream event of lipid
• Sepsis
• Solid-organ transplantation peroxidation. However, this might explain the spread of RN
• Stroke from one cell to another in a functional unit, which is a unique
• Transplant rejection feature of ferroptosis. NADPH drifts freely between neighboring
cells through intercellular pores, such as gap junctions, that may
give rise to a diffusion drag, leading to RCD in adjacent cells. 17,18
Necroptosis critically contributes to diverse pathophysiological Ferroptosis and synchronized RN are both active in the
settings, such as ischemia–reperfusion injury in solid organ urogenital tract and synchronized organs, such as the brain and
transplantations, myocardial infarction, stroke, and SIRS. RIPK3- the heart. This has led to the hypothesis that the physiological
and MLKL-deficient mice have been demonstrated to be protected role of ferroptosis may be preserved for obliteration processes
from preclinical models of such diseases by several independent similar to those of the paramesonephric (Müllerian) duct.
groups, so inhibitors of necroptosis (RIPK1 kinase inhibitors, At the time of writing this chapter, no immunomodulatory
RIPK3 kinase inhibitors, and MLKL inhibitors) have entered role for cells that die by ferroptosis had been described, and the
phase I and phase II clinical trials. No cell death–preventing immunogenicity of ferroptosis is certainly high. In contrast to
therapy has been approved by the US Food and Drug Administra- the more immunogenic pyroptosis and the less immunogenic
tion (FDA) as of the writing of this chapter. However, preclinical necroptosis, ferroptosis may thus be a prototype cell death that
and first clinical data are very promising. Necroptosis inhibitors leads to inflammation induced by DAMPs in the classic sense.
may soon become the first-in-class compounds to prevent RN. 13 However, it cannot be excluded that the lipid peroxidation and
the high concentrations of ROS that are released into the extracel-
Ferroptosis lular space function as proinflammatory stimuli.
Ferroptosis is an important RN pathway in ischemic injury and
cancer. Unlike extrinsic apoptosis and necroptosis, it is not initi- Mitochondrial Necrosis
ated by specific receptors. In renal tubules, it mediates an event Mitochondrial necrosis is largely a mystery. Clear data exist to
referred to as synchronized regulated necrosis of an entire functional demonstrate that widespread depletion of mitochondria does
19
unit. It thus provides a biochemical basis for the clinical observa- not affect necroptosis and that RIPK3 depletion does not affect
20
tion of necrotic casts in the urine sediment of patients with parthanatos. Thus necroptosis does not require mitochondria,
acute kidney injury. Ferroptosis key molecules have been associ- and mitochondrial cell death does not require RIPK3. However,
ated with renal clear cell carcinomas. Ferroptosis is critically almost any other RN pathway is, to some extent, affected by
mediated by the loss of NADPH (the major cellular redox mitochondrial dynamics. Most models consider the release of
equivalent) abundance as result of lipid peroxidation. This the so-called apoptosis-inducing factor (AIF, clearly a misnomer)
peroxidation is actively mediated by lipoxygenase ALOX5 and from mitochondria as a necrosis-inducing outcome. The detailed
glutathione peroxidase 4 (GPX4) seems to be its major coun- mechanisms about AIF-induced necrosis are unclear. Evidence
terpart. Upon dysfunction of GPX4, ferroptosis occurs rapidly from isolated mitochondria, as well as from immunofluorescence