Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. 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. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune 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 of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.
The signaling pathway responsible for carrying out necroptosis is generally understood. TNFα leads to stimulation of its receptor TNFR1. TNFR1 binding protein TNFR-associated death protein TRADD and TNF receptor-associated factor 2 TRAF2 signals to RIPK1 which recruits RIPK3 forming the necrosome also named ripoptosome. Phosphorylation of MLKL by the ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles. Integration of MLKL leads to the inflammatory phenotype and release of damage-associated molecular patterns (DAMPs), which elicit immune responses.
Function
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.
In innate immunity
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 by phagocytosis. Some pathogens, such as human cytomegalovirus, express caspase inhibitors that arrest the apoptotic machinery of the host cell. The caspase-independence of necroptosis allows the cell to bypass caspase activation, decreasing the time during which the pathogen can inhabit the cell.
Toll-like receptors (TLRs) can also signal to the necrosome, leading to necroptosis. TLRs are a class of receptors that function in the innate immune system to recognize conserved components of pathogens, such as flagellin.
In contrast to apoptosis
In apoptosis, extrinsic signaling via cell surface receptors or intrinsic signaling by release of cytochrome c from mitochondria leads to caspase activation. Proteolytic degradation of the cell's interior culminates with the packaging of the cell's remains into apoptotic bodies, which are degraded and recycled by phagocytosis. 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.