Why is apoptosis safer than necrosis

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In physiological conditions, they respond to trophic factors and act as an anti-apoptotic stimulus. However, when their ligand falls below a certain level in the extracellular space, ligand-free receptors trigger the apoptotic response. BAK is a transmembrane protein of the outer mitochondrial membrane. Upon apoptosis induction, BAX undergoes conformational change. This exposes its transmembrane domain, leading to the insertion of BAX into the outer mitochondrial membrane.

Apoptosis is reflected in significant cell morphological changes Table 1. In the earlier phases, a cell undergoing apoptosis loses cell contacts and changes shape. Chromatin condenses in the nucleus and moves toward the nuclear envelope.

Condensation of the nucleus pyknosis initiates DNA degradation. Loss of water results in significant cell shrinkage and blebbing of the plasma membrane with little or no morphological changes to the other cellular organelles. Phosphatidylserine, a lipid present only in the inner layer of the plasma membrane, is now also visible in the outer layer. Nucleus and cytoplasm fragment into apoptotic bodies.

Released cellular proteases lead to disintegration of the cellular skeleton, membranes, and proteins. Neighboring macrophages recognize, engulf, and digest apoptotic bodies, completing the process. What is necrosis? Necrosis is a form of cell injury defined as unregulated cell death resulting from internal or external stresses such as mechanistic injuries, chemical agents, or pathogens.

The process is usually rapid and leads to cell swelling oncosis and bursting due to loss of osmotic pressure Table 1. During necrosis, the loss of plasma membrane integrity induces cellular contents to escape to the extracellular space, causing inflammatory responses. Cell disintegration is preceded by a series of morphological changes, including disruption of cell organelles, such as swelling of the ER and mitochondria, or decay of the Golgi apparatus. An influx of calcium ions from the extracellular matrix activates intracellular nucleases that fragment DNA.

Freed lysosomal hydrolases contribute to the degradation of nucleic acids and proteins. Decay products activate leukocytes, lymphocytes, and macrophages that phagocytose the remnants of dead cells. Necroptosis is a form of regulated cell death that produces necrotic phenotype.

It arises in response to stress stimuli PMID: ; 6 , ; 7 , and ; 8 such as interferons, death ligands, or Toll-like receptors. Figure 4. Figure 5. Autophagy is a natural degradation process of cellular contents during nutrient stress.

In the case of macro-autophagy, it involves the formation of double membrane vesicles called autophagosomes that fuse with lysosomes to form autolysosomes. This process is initiated by the mechanistic target protein of rapamycin mTOR and autophagy-related genes Atgs proteins Figures Autophagy promotes cell survival, providing starved cells with nutrients obtained through the digestion of non-essential cellular components.

It was discovered that macro-autophagy can also be one of the routes for programmed cell death PMID: ; 2. Although significantly less common than apoptosis, it plays a role in regulating some developmental processes.

The most well known is the removal of certain larval organs — the salivary glands and midgut — in Drosophila melanogaster during larval—pupal transition PMID; 3 and ; 4.

Until recently, necrosis has been considered a solely accidental and non-programmed cell death modality. However, extensive genetic and pharmacological studies have clearly demonstrated that cells can and do undergo programmed necrotic processes, such as necroptosis, pyroptosis, ferroptosis, and NETosis Fig.

Despite several shared morphological features, each programmed necrotic pathway utilizes distinct molecular process and generates different immunological outcomes. Since programmed necrosis is closely associated with multitude of inflammatory and autoimmune diseases, thorough understanding of these mechanisms is needed to identify effective therapeutic targets for disease [ 9 , 24 ].

Molecular pathways of cell death and their roles in inflammation. Depending on death stimuli and context, live cells can undergo apoptosis or programmed necrosis. In the absence of effective clearance, apoptotic cells are proceeded to secondary necrosis and elicit some inflammatory responses.

Upon damage signals such as infection or metabolic stress, cells trigger genetically programmed necrosis. In contrast, ferroptosis is triggered by lipid peroxidation, and shows damaged mitochondria and reduced cellular volume.

Programmed necrotic cells generally release DAMPs and inflammatory cytokines that stimulate innate immune cells and promote necroinflammation. Indeed, engagement of aforementioned death receptor pathways can trigger necroptotic cell death in the absence of caspase 8 activity, via RHIM-containing kinases like receptor-interacting protein kinase 1 RIPK1 and RIPK3 [ 26 , 27 ].

Death receptor-induced necroptosis is currently the most deeply characterized necrotic pathway. Auto- and trans-phosphorylation of RIPK1 and RIPK3 enables recruitment and activation of the pseudokinase, mixed lineage kinase-like MLKL , followed by oligomerization, binding to plasma membrane-associated phosphatidylinositol phosphates, and the disruption of plasma membrane integrity [ 26 , 36 , 37 ]. A recent study showed that ESCRT-III regulates the dynamics and kinetics of plasma membrane integrity during necroptosis, thus modulating the level of DAMPs release to facilitate an appropriate subsequent adaptive immune response [ 39 ].

As a consequence of plasma membrane rupture, extracellular DAMPs and cytokines affect neighboring cells and trigger inflammation via signaling through their cognate receptors [ 40 ]. Indeed, necroptotic cells release many types of DAMPs including HMGB1, nucleic acids, IL-1 family members, ATP, uric acid, and S protein, which contribute to the activation of innate immune cells like dendritic cells and macrophages [ 13 , 40 ], although IL seems to dampen inflammation through modulating regulatory T cells [ 13 , 24 ].

I n vivo evidence for necroptosis and its pathophysiological role is also rapidly accumulating. Recent studies indicate that necroptosis is very common during damage associated with physical trauma, infection, neurodegeneration, and ischemia. Despite the capacity of necroptosis to induce inflammation, emerging evidence suggests that the main pathological role of necroptosis is host defense.

The phenotypic discrepancies observed between RIPK3- and MLKL-deficient mice support the idea of necroptotic machinery being a critical component of inflammation, beyond the function of necroptosis [ 42 , 43 ]. RIPK3-deficient mice display enhanced protection against ischemic injury and sterile sepsis models via cell death-independent mechanisms, and RIPK3 deficiency also limits viral pathogenesis of West Nile Virus WNV independently of cell death [ 44 , 45 ]. Together, these results imply that RIPK3 has a role in regulating inflammation and the immune response independently of MLKL activation and necroptosis.

Pyroptosis from the Greek, pyro meaning fire , which is another form of programmed cell death mediated by excessive inflammasome activation and displays features common to both apoptosis caspase dependence, chromatic condensation, and DNA fragmentation and necrosis cellular swelling, plasma membrane pore formation, and membrane rupture [ 14 , 47 , 48 ].

Ferroptosis exhibits unique morphological changes, like decreased cell volume and damaged mitochondria. Apoptotic features DNA fragmentation, membrane blebbing or necrotic features oncosis, necrotic membrane rupture are largely absent in ferroptosis [ 54 ].

Despite this, ferroptosis can still potently induce inflammation via the release of HMGB1, IL, and other unidentified pathways [ 54 , 55 ]. This imbalance results in a depletion of intracellular GSH and inhibition of GPX4, the net effect being high intracellular levels of H 2 O 2 and excessive lipid peroxidation, ultimately causing cell death in a manner independent of apoptotic or necroptotic machinery [ 54 , 55 , 56 ].

Intracellular cysteine availability is a rate-limiting step for GSH synthesis, and inhibiting the exchange of cystine for glutamate through the antiporter is critical for the initiation of ferroptosis. Thus, excessive level of extracellular glutamate may trigger ferroptosis under physiological conditions [ 57 ].

In some cells, cysteine can be biosynthesized via the trans-sulfuration pathway using methionine, resulting in ferroptotic resistance [ 58 ]. Importantly, PUFAs are highly susceptible to lipid peroxidation, and the accumulation of PUFA hydroperoxides proves to be the lethal step in ferroptosis, as lipid peroxides can be broken into lipid radicals that react with proteins and nucleic acids [ 55 ].

Silencing of iron-responsive element-binding protein 2 IREB2 , a master regulator of iron metabolism, decreases ferroptosis [ 54 ], while selective autophagic clearance of ferritin enhances susceptibility of ferroptosis by releasing free iron [ 60 , 61 ].

Neutrophils are a short-lived but critical component at the frontline of host defense. In addition to phagocytosis, neutrophil produce and release of antimicrobiocidal granule contents degranulation , ROS oxidative bursts and neutrophil extracellular traps NETs [ 62 ]. NETs are web-like structures comprised of decondensed chromatin bound to cytosolic and granular proteins. The NETs are able to trap, immobilize, inactivate, and kill microorganisms, as well as stimulate the immune response [ 62 , 63 ].

Following the disintegration of the nuclear envelope, the chromatin decondensation process expands into the cytoplasm of living cells, where DNA and cytoplasmic and granular components co-mingle. In vitro studies have demonstrated that, in addition to DNase I, macrophages play an important scavenging role in NET clearance [ 66 ].

The morphology of NETosis suggests that this type of cell death is pro-inflammatory, owing to its lytic nature and the release of histones, nucleic acids, and cytotoxic granular molecules. However, the immunological consequences of NETosis remain controversial as it is also suggested that NETs can help resolve local inflammation at a high concentration [ 68 ]. For decades, efferocytotic research focused on the clearance of apoptotic cells, considered the archetypal programmed cell death.

The apoptotic cell packages itself into immunologically inert pieces and promotes its own removal via the active advertising of its presence.

Thus, the efferocytosis of apoptotic cells can be viewed as the gold standard of dying cell clearance, as the mechanisms underlying apoptosis and efferocytosis are rooted in effective immunotolerance [ 71 ]. Efferocytosis is a coordinated event, wherein dying cells recruit, prime, and present themselves to both professional phagocytes macrophages and dendritic cells and non-professional phagocytes epithelial cells.

Thus, PS exposure acts as a first line mechanism to preemptively clear dying cells before secondary necrosis and the release of DAMPs occurs. Phagocytes are armed with receptors that allow them to sense and migrate to areas of cell death, as well as recognize and internalize cellular corpses for degradation and processing [ 71 ]. Different tissues preferentially express different PSRs including BAI1 bone marrow, spleen, brain , TIM4 kidney , and stabilin-2 sinusoidal endothelial cells , suggesting tissue-specific PS receptor mechanisms [ 71 , 74 , 82 ].

While downstream molecules used by specific PSRs can differ and are discussed in greater detail here [ 14 ] , engulfment mediated by PSRs activates the Rho family of small GTPases, converging on evolutionarily conserved Rac1 [ 14 ].

Once engulfed, phagocytes must degrade, digest, and process their cellular corpse cargo. Rab5 and Rab7, small GTPases, are recruited to the phagosome to mediate fusion to the lysosomal network, which contains acidic proteases and nucleases that digest cellular corpses into their basic factors [ 14 ]. A recently described form of non-canonical autophagy, termed LC3-associated phagocytosis LAP , was found to be crucial for the homeostatic clearance of dying cells, as well as shaping the appropriate immune response during efferocytosis [ 69 , 70 ].

While LAP can be triggered by pathogen sensing viaTLRs or FcR during uptake, LAP is also activated by PSR engagement during efferocytosis, resulting in the recruitment of a distinct subset of autophagic machinery to the cargo-containing, single-membraned vesicle [ 69 , 83 ]. LAP requires the activity and localization of Rubicon RUN domain protein as Beclin-1 interacting and cysteine-rich containing , whereas canonical autophagy induced by starvation or rapamycin treatment is Rubicon-independent [ 84 ].

LAP facilitates the rapid destruction of the engulfed cargo via fusion with the lysosomal pathway and is crucial in mediating the immunotolerant response associated with efferocytosis [ 69 , 83 , 84 ]. Activation of these factors mediates the upregulation of other phagocytic machinery, such as the TAM family, and basal cholesterol efflux machinery, such as ABCA1 ATP-binding cassette subfamily A, member 1 , to accommodate this increase in cholesterol levels [ 87 ].

Despite the multi-step process by which efferocytosis occurs, and the functional redundancy of some of the key players, defects in even a single component of this pathway can have deleterious effects, often resulting in autoinflammation or autoimmunity [ 11 ], highlighting the importance of this pathway in homeostasis. The efficiency with which efferocytosis operates underscores the danger of exposure to DAMPs [ 90 , 91 ]. The immunotolerant beauty of apoptosis lies in its sequestration of cellular contents into membrane-bound blebs which isolates DAMPs from their cognate PRRs.

The developmentally and functionally homeostatic process of apoptosis is therefore akin to the nuclear compartmentalization of nucleic acids, permitting the evolution of viral nucleic acid sensors, which are critical for host defense [ 94 ]. Programmed necrosis, however, unleashes intracellular and immunostimulatory DAMPs on to phagocyte PRRs, eliciting inflammation and if left unchecked, autoimmune and autoinflammatory disorders Fig. The lytic nature of programmed necrosis means that its debris is inadvertently PS-positive, and necroptotic and pyroptotic cells can and do engage PSRs [ 10 ].

Despite providing the excess cholesterol and fatty acids that tend to suppress inflammation by apoptotic cells, efferocytosis of necrotic cells does not mediate the same immunotolerant response [ 69 ]. Systemic spread of necroinflammation. Programmed necrosis or defective efferocytosis of dying cells can initiate local inflammation. DAMPs and proinflammatory cytokines derived from necrotic cells and subsequently activated immune cells provide feed-forward signals reinforcing programmed necrosis in more cells.

Continuing the vicious death cycle allows the damage of barrier function, the spread of necroinflammation to systemic level, which may ultimately cause devastating multi-organ failure. Programmed necrosis, however, is not solely a losing game. Programmed necrosis can be triggered by an immunologically calamitous event, such as infection.

In situations that require immune attention, these programmed necrotic pathways have likely evolved to modulate the immune response. During pyroptosis, pore-induced intracellular traps PITs can trap intracellular bacteria within structures and complement and scavenger receptor stimulation can promote the PIT clearance by neutrophils. Therefore, pyroptosis and necroptosis may represent two unique biological pathways in which the host counteracts pathogen evasion mechanisms [ 97 ].

Programmed necrosis has a crucial role in defending against invading microorganisms and regulating innate immunity. However, its activity may be a double-edged sword in human pathophysiology, as it is involved in the development of a variety of chronic inflammatory and autoimmune diseases via different mechanisms Table 2. Mice lacking RIPK3 are highly susceptible to bacterial Yersinia pestis [ 99 ] and viral pathogens [ ], often accompanied by defective pathogen-induced tissue necrosis [ 35 ].

These results suggest that control of these viruses in vivo may depend on RIPK3-directed transcriptional responses instead of necroptosis. Treatment with the RIPK1 kinase inhibitor, Necrostatin-1, or genetic ablation of RIPK3 effectively protects against brain and kidney ischemia [ , ], renal allograft inflammation [ ], and myocardial infarction [ , ].

Pyroptosis acts as a protective host mechanism against microbial infections, via destruction of its replication niche. Inflammasome-defective mice are more susceptible to bacterial, viral, or fungal challenge [ 97 ]. Recent studies indicate that parasites can also trigger pyroptosis via inflammasome activation [ ].

While inflammasome complexes are essential for pathogen clearance, their uncontrolled and excessive activation is detrimental and pathogenic. Over-activation of pyroptosis by pathogens can lead to widespread cell death, acute organ failure, sepsis, and septic shock [ ]. Ablation of the key enzyme, GPX4, in the ferroptosis pathway results in embryonic lethality in mice, implying an important role of ferroptosis in development [ ].

In addition, conditional deletion of GPX4 in murine neuronal cells caused rapid motor neuron degeneration, and inducible GPX4 ablation in adult mice led to neuronal loss and inflammation in the hippocampus [ , ]. Increased levels of hepcidin, a regulator of iron release, was involved in ischemic brain injury, and its silencing ameliorated damage [ ]. Furthermore, renal tubular cells are particularly sensitive to ferroptosis in GPX4-deficient mice [ ].

Consistently, highly reactive catalytic iron is considered as a risk factor for acute kidney injury AKI , and the treatment with iron chelators, like desferrioxamine, displayed some protective effect despite inconsistency [ 13 ]. In addition, ferritin, hepcidin, and heme oxygenase 1 are all involved in the pathogenesis of AKI [ 24 ].

Human patients deficient for MPO, a key neutrophilic enzyme, have an increased risk for Candida albicans infection [ ]. Similarly, MPO deficient mice also failed to clear C. Despite its role in controlling infection, NETs are now considered a source of self-antigen and a potential initiator in many autoimmune diseases, including SLE [ ], rheumatoid arthritis RA [ ], anti-neutrophil cytoplasmic antibody ANCA -associated vasculitis AAV [ ] and type 1 diabetes T1D.

Paradoxical as it may seem, life requires death — for the proper development of an organism, for the regeneration of tissue and cells over time, and for the appropriate immune response during challenge. These newly characterized pathways represent possible targets for therapies against inflammatory diseases and infections that have often been refractory to current treatments.

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