Nonapoptotic forms of cell death
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P192-193
2025-11-11
30
Necroptosis
Necroptosis (necrosis-like cell death) is a form of caspase-independent programmed cell death that is important in inflammation and viral infection. Necroptosis can be initiated by death receptors, such as FAS and TNFR1, TLR3 and TLR4, which recognize pathogens (double-stranded RNA viruses or lipopolysaccharides, respectively), or by the intracellular nucleic acid sensor ZBP1. Necroptosis is dependent on the activation of RIPK1 and RIPK3; the latter phosphorylates and activates the effector molecule mixed-lineage kinase domain-like protein (MLKL). Phosphorylated MLKL oligomerizes and disrupts the plasma membrane through exposing phospholipids to trigger cell mem brane permeabilization and cellular destruction. The cell then dies by necroptosis, a process characterized by necrosis-like features, which include cell swelling, membrane disruption, and the release of the intra cellular contents. Death-receptor triggered necroptosis can only proceed when the caspase-8–c-FLIP complex is inhibited because caspase-8 can cleave RIPK1 and RIPK3, preventing necroptosis. Inhibition of caspases is observed during certain viral infections, in which case necroptosis proceeds as a dominant cell death pathway. Importantly, necroptotic cells release damage-associated molecular patterns (DAMPs) that can induce inflammatory responses. They activate caspase-1, which in turn cleaves proinflammatory interleukin (IL)-1β and IL-18 into mature inflammatory forms. Release of IL-1β is dependent on RIPK3 through caspase-8 or an MLKL-dependent NLRP3 inflammasome. Among the three NLR inflammasomes, NLRP1 and NLRC4 inflammasomes recognize bacterial muramyl dipeptide and flagellins, respectively, while NLRP3 recognizes multiple stimuli, including saturated fatty acids, bacterial RNA, and urate crystals. An inflammatory cell death termed pyroptosis (see below) is initiated by inflammasome activation. Recent findings suggest that dysregulated necroptosis during hematopoiesis promotes bone marrow progenitor cell death that induces inflammation, impairs hematopoietic stem cells, and recapitulates the features of the bone marrow failure disorder myelodysplastic syndrome (MDS). Genetic loss of Ripk1 in hematopoietic cells can be responsible for this bone marrow failure. In cancer, necroptosis may facilitate metastasis through damaging endothelial cells.
Ferroptosis
Ferroptosis is an iron-dependent form of regulated necrosis. In ferroptosis, lipid peroxidation occurs in the presence of free iron, which reacts with hydrogen peroxide produced by reactive oxygen species (ROS), a reaction that is further fueled by lipid oxidation in the presence of oxygen and the disruption of cellular membranes. The physiological role of ferroptosis in development and homeostasis remains to be elucidated. Ferroptotic cells exhibit a necrotic-like phenotype, including mitochondrial shrinkage, disrupted cristae, and a ruptured outer mitochondrial membrane, yet these features occur independently of caspase activation or necrosis. Ferroptosis is inhibited by the lipid peroxidase GPX4, which in turn requires glutathione and NADPH for recycling. Accordingly, ferroptosis can be observed under conditions of cysteine/ cystine deprivation or inhibition of the cystine/glutamate antiporter Xc- (i.e., by sorafenib) because these interfere with glutathione syn thesis. Reduction in NAPDH or inhibition of GPX4 (i.e., by the alkylator altretamine) can also induce ferroptosis. Ferroptosis was first discovered in cancer cells treated with the VDAC2/3 inhibitor erastin, which causes ferroptosis by promoting iron-dependent ROS accumulation. Ferroptosis can be blocked by depletion of free iron (i.e., iron chelation), inhibition of synthesis of polyunsaturated fatty acids, or ROS scavenging using lipophilic antioxidants such as ferrostatin-1. Identification of agents that can selectively induce ferroptosis is actively being pursued in cancer research.
Pyroptosis
Pyroptosis is a cell-intrinsic inflammatory form of regulated cell death in response to bacterial, viral, fungal, and protozoan infections. It occurs upon cleavage and oligomerization of the effector molecule gasdermin D (GSDMD), which executes pyroptosis via forming large pores in the membranes. Pyroptosis requires activation of caspases distinct from those involved in apoptosis, including caspase-1 and caspases-4 and -5 in humans and their rodent homolog caspase-11. Caspases-4, -5, and -11 are directly activated by cytosolic lipopolysaccharides from invading gram-negative bacteria and cleave GSDMD in monocytes and other cell types, triggering pyroptosis. In turn, activation of caspase-1 by pathogen-associated pattern recognition receptors like the NLRs and the cytosolic DNA sensor AIM2—or in some instances indirectly through an adapter protein, apoptosis-associated speck-like (ASC) protein—leads to formation of inflammasomes, caspase-1–mediated cleavage of GSDMD, and processing of the cytokines IL-1β and IL-18, which can be released through GSDMD pores.41 Additional members of the gasdermin family were recently identified as media tors of pyroptosis, one of which, GSDME (also known as DFNA5), is cleaved by caspase-3 that has been activated by TNF or chemotherapy drugs and could be responsible for normal tissue toxicity from chemotherapy. Further characterization of caspase-3 as an activator of GSDME/DFNA5 broadened the role of this type of cell death, which has been recently shown to augment mitochondrial apoptosis.
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