Necroptosis

Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system.

[5][6] Integration of MLKL leads to the inflammatory phenotype and release of damage-associated molecular patterns (DAMPs), which elicit immune responses.

TLRs are a class of receptors that function in the innate immune system to recognize conserved components of pathogens, such as flagellin.

[8] Necrotic cells are cleared from the immune system by a mechanism called pinocytosis, or cellular drinking, which is mediated by macropinosomes, a subcellular component of macrophages.

Furthermore, RIPK1 can be regulated by cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1, cIAP2) which polyubiquitinate RIPK1 leading to cell survival through downstream NF-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.

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.

Treatment with the drug cyclosporine, which represses the mitochondrial permeability transition effector Cyclophilin 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.