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Necroptosis is a programmed form ofnecrosis and one of the many modalities ofprogrammed cell death that has been described insofar.[1] Conventionally, necrosis is associated damage caused by traumatic external forces, such as mechanical damage, heat, osmotic pressure and disruption by certain parasites. In contrast to orderly, programmed cell death viaapoptosis, necrosis in this sense doesn't involve biological processes happening within the cell. The content of the cell only matters after its death: released into the extracellular environment, some molecules which are otherwise only present in intracellular compartments can be detected by other cells. Labelled asdamage-associated molecular patterns (DAMPs), these molecules serves as sentinel of tissue damage, incurring corresponding responses from the recipient cells. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Necrotic death might be favourable for its speedy induction of cell-level reaction, represented by the multi-faceted orchestrated response ofimmune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence ofviral caspase inhibitors to restrict virus replication.[2] In addition to being a response to disease, necroptosis has also been characterized as a component ofinflammatory diseases such asCrohn's disease,pancreatitis, andmyocardial infarction.[3][4]
The signaling pathway responsible for carrying out necroptosis is generally understood.TNF leads to stimulation of its receptorTNFR1. TNFR1 binding protein TNFR-associated death proteinTRADD and TNF receptor-associated factor 2TRAF2 signals toRIPK1 which recruitsRIPK3 forming the necrosome also named ripoptosome.[2] Phosphorylation ofMLKL by the ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles.[5][6] Integration of MLKL leads to the inflammatory phenotype and release of(DAMPs), which elicit immune responses.
Necroptosis is specific to vertebrates and may have originated as an additional defense to pathogens. Necroptosis also acts as an alternative "fail-safe" cell death pathway in cases where cells are unable to undergo apoptosis, such as during viral infection in which apoptosis signaling proteins are blocked by the virus.
Cell suicide is an effective means of stemming the spread of a pathogen throughout an organism. In apoptotic responses to infection, the contents of an infected cell (including the pathogen) are contained and engulfed byphagocytosis. Some pathogens, such ashuman cytomegalovirus, expresscaspase inhibitors that arrest the apoptotic machinery of the host cell.[7] The caspase-independence of necroptosis allows the cell to bypass caspase activation, decreasing the time during which the pathogen can inhabit the cell.
Under certain circumstances, TLR3 and TLR4 which belongs to the groupToll-like receptors (TLRs) can also give rise to necroptosis in response to bacterial and viral infection-related molecular signals, such as LPS and cytosolic dsDNA[2] . The TLRs signaling leads to the formation of "necrosome" comprising RIPK1 and RIPK3, which recruits and activates MLKL. Standing alone from the TLRs and TNF superfamily members, ZBP1, a cytosolic DNA-recognising protein can also provide the stimulus for necroptosis. As the final executioner of necroptotic cell death, activated MLKL oligerises, inserts into and therefore rupture cell membrane, causing the divulging of cellular content and the death of the cell.[8]
Inapoptosis, extrinsic signaling via cell surface receptors or intrinsic signaling by release ofcytochrome c frommitochondria leads to caspase activation. Proteolytic degradation of the cell's interior culminates with the packaging of the cell's remains intoapoptotic bodies, which are degraded and recycled byphagocytosis. Unlike in apoptosis, necrosis and necroptosis do not involve caspase activation. Necrotic cell death culminates in leakage of cell contents into the extracellular space, in contrast to the organized disposal of cellular contents into apoptotic bodies.[9]
As in all forms of necrotic cell death, cells undergoing necroptosis rupture and leak their contents into the intercellular space. Unlike in necrosis, permeabilization of the cell membrane during necroptosis is tightly regulated. While many of these mechanisms and components of the pathway are still being uncovered, the major steps of necroptotic signaling have been outlined in recent years.[when?] First, extrinsic stimulus through the TNF receptor by TNFα signals the recruitment of the TNF receptor-associated death domain (TRADD) which in turn recruitsRIPK1. In the absence of active caspase 8, RIPK1 and RIPK3 auto- and transphosphorylate each other, leading to the formation of a microfilament-like complex called the necrosome.[2] The necrosome then activates the pro-necroptotic proteinMLKL via phosphorylation. MLKL actuates the necrosis phenotype by inserting into the bilipid membranes of organelles and plasma membrane leading to expulsion of cellular contents into the extracellular space.[5][6] The inflammatory rupturing of the cell releases damage associated molecular patterns (DAMPs) into the extracellular space. Many of these DAMPs remain unidentified, however, the "find me" and "eat me" DAMP signals are known to recruit immune cells to the damaged/infected tissue.[9]
Recent studies have shown substantial interplay between the apoptosis and necroptosis pathways. At multiple stages of their respective signalling cascades, the two pathways can regulate each other. The best characterized example of this co-regulation is the ability of caspase 8 to inhibit the formation of the necrosome by cleaving RIPK1. Conversely, caspase 8 inhibition of necroptosis can be bypassed by the necroptotic machinery through the anti-apoptotic protein cFLIP which inactivates caspase 8 through formation of a heterodimer.[4]
Many components of the two pathways are also shared. The tumor necrosis factor receptor can signal for both apoptosis and necroptosis. The RIPK1 protein can also signal for both apoptosis and necroptosis depending on post-translational modifications mediated by other signalling proteins. Furthermore, RIPK1 can be regulated by cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1, cIAP2) which polyubiquitinate RIPK1 leading to cell survival through downstreamNF-kB signalling. cIAP1 and cIAP2 can also be regulated by the pro-apoptotic protein SMAC (second mitochondria-derived activator of caspases) which can cleave cIAP1 and cIAP2 driving the cell towards an apoptotic death.[2]
Cells can undergo necroptosis in response to perturbedhomeostasis in specific circumstances. In response toDNA damage, the RIPK1 and RIPK3 are phosphorylated and lead to deterioration of the cell in the absence of caspase activation. The necrosome inhibits the adenine nucleotide translocase in mitochondria to decrease cellularATP levels.[9] Uncoupling of the mitochondrial electron transport chain leads to additional mitochondrial damage and opening of the mitochondrial permeability transition pore, which releases mitochondrial proteins into the cytosol. The necrosome also causes leakage of lysosomal digestive enzymes into the cytoplasm by induction of reactive oxygen species by JNK, sphingosine production, and calpain activation by calcium release.
Necroptosis has been implicated in the pathology of many types of acute tissue damage, including myocardial infarction, stroke, ischemia-reperfusion injury. In addition, necroptosis is noted to contribute to atherosclerosis, pancreatitis, inflammatory bowel disease, neurodegeneration, and some cancers.[10] It has also been implicated in Alzheimer's disease triggered by the production ofMEG3 in the brain cells.[11][12]
In solid-organ transplantation,ischemia-reperfusion injury can occur when blood returns to tissue for the first time in the transplant recipient. A major contributor to tissue damage results from activation of regulated necroptosis, which could include contributions from both necroptosis and mitochondrial permeability transition. Treatment with the drugcyclosporine, which represses the mitochondrial permeability transition effectorcyclophilin D, improves tissue survival primarily by inhibiting necrotic cell death, rather than its additional function as an immunosuppressant.[4]
Recently, necroptosis-based cancer therapy, using a distinctive molecular pathway for regulation of necroptosis, has been suggested as an alternative method to overcome apoptosis-resistance. For instance, necroptotic cells release highly immunogenicDAMPs, initiatingadaptive immunity. These dying cells can also activateNF-κB to expresscytokines, recruitingmacrophages.[13] As of 2018[update] little is known aboutnegative regulators of necroptosis, butCHIP,cFLIP andFADD appear to be potential targets for necroptosis based therapy.[13]