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receptor-interacting protein 3 (RIP3) and caspase-8 dependent necroptosis, which mobilize immune cells
to form Complex II. Active caspase-8 can cleave against viruses. Therefore, in certain virus-infected
[21]
[10]
and inactivate RIP1 and RIP3, thereby promoting the diseases, necroptosis seems to be an evolutionarily
exogenous apoptosis pathway. [11] cellular anti-virus strategy.
If caspase-8 is inhibited, RIP1 and RIP3 will remain In terms of bacterial infection, it has long been
active and combine together by the common RHM known that TNF is an important driver of bacterial
domain to take part in forming a necrosome, which sepsis, suggesting that necroptosis may also be a
[22]
initiates a downstream signal cascade resulting in pro-inflammatory factor in the bacterial infection-
necroptosis. Although RIP1 and RIP3 are both induced inflammation. In consistent with above
[12]
essential in the process, over-expressed RIP3 can mentioned role of RIP/MLKL-dependent necroptosis
induce necroptosis without enough RIP1, but not vice in the destructive inflammation after virus infection,
versa. It has been demonstrated that RIP3 activates RIP3 deficient mice are more resistant to TNF induced
[13]
downstream signalling pathways, in particular, the systematic inflammation. However, some studies
[23]
phosphorylated mixed lineage kinase domain-like showed that RIP3 macrophages respond almost
-/-
protein (MLKL), which plays a central role in the normally to liters per second stimulation, indicating
[14]
execution of necroptosis. Two models have been that RIP3 may not be crucial for acute inflammation
proposed for its function: (1) acts as a platform at the after bacterial infection. In line with this idea,
[24]
plasma membrane for the recruitment of Ca or Na + RIP3-dependent necroptosis and TNF expression was
2+
ion channels, (2) as a direct pore-forming complex observed in tuberculosis infected tissue, suggesting
[15]
[25]
on cell membranes through binding of the amino- a role of necroptosis in the bacterial induced chronic
terminus of the 4-helical bundle domain to negatively inflammation.
charged phosphatidylinositol phosphates. Previous
[16]
studies have suggested that phosphoglycerate mutase In addition to its roles in infectious diseases, necroptosis
5 involved mitochondrial fragmentation might be the has also been demonstrated to be involved in chronic
key downstream molecule of MLKL for necroptosis sterile inflammation. For example, up-regulation
execution. [17] However, recent evidences have of RIP3 and phosphorylated MLKL were detected
challenged this idea. [18] in alcoholic and drug-induced liver injury. RIP3
depletion, or necrostatin-1 (Nec-1) administration can
The mechanism of necroptosis discussed above is significantly protect liver cells from these injuries.
[26]
outlined in Figure 1. Besides the TNF-α induced In ischemia-reperfusion conditions, necroptosis was
extrinsic necroptosis, an intrinsic necroptosis signalling reported in multiple tissues, including brain, heart,
initiated by intracellular reactive oxygen species has kidney and retina. [27-29] In other chronic inflammatory
been proposed recently. Translocation of p53 has been diseases such as atherosclerosis, receptor-interacting
suggested to play a role in ischemia induced intrinsic serine/threonine-protein kinase 3-dependent
necroptosis. More detailed mechanisms of intrinsic macrophage necroptosis has been thought of as a direct
[19]
necroptosis remain to be elucidated. driver of atherosclerotic plaque formation. Although
[30]
it has been clearly demonstrated that necroptotic
NECROPTOSIS AND INFLAMMATION cells release DAMPs, how DAMPs mediate this
necroptosis-triggered sterile inflammation remains to
It is known that apoptosis triggers minor or no be experimentally validated.
inflammation, while necrosis induces inflammation
via releasing damage associated molecular patterns It should be pointed out that many studies used Nec-1
(DAMPs), such as nuclear high mobility group box- to inhibit necroptosis. However, recent studies reported
1 proteins, mitochondrial DNA, and IL-1 family that Nec-1 has off-target effects. Besides inhibiting
cytokines. The insertion of MLKL into cell the kinase activity of RIP1, it inhibits the activity of
[20]
membranes immediately suggested a possible role endoleamine 2,3-oxygenase, which by itself, modulates
of MLKL in the release of DAMPs. Because DAMPs inflammation. [31] Therefore, one should be sure to
stimulate pattern-recognition receptors such as toll- explain the results obtained solely by Nec-1 treatment.
like receptors, necroptosis is thought to be beneficial
in innate immune responses. For example, vaccinia NECROPTOSIS AND NEUROLOGICAL DISEASES
virus encodes an inhibitor of caspase-1 and 8. In cases
of vaccinia virus infection, the cells exhibit RIP3- Necroptosis was initially identified in ischemic brain.
158 Neuroimmunol Neuroinflammation | Volume 3 | July 8, 2016