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As the molecular mechanisms of necroptosis have been we know, inflammation is complex and dynamic. The
gradually discovered, necroptosis has been reported in outcome of inflammation depends on the coordination
more and more neurological diseases. of different types of immune cells. Even sub-
populations of immune cells change their phenotypes
Spinal cord injury (SCI) is well known for its in the course of inflammation, such as the M1-M2
devastating effects on patients. One pathological feature switch of microglia/macrophages. How necroptotic
[40]
of SCI is secondary injury characterized by chronic cells affect the different immune cell populations
inflammation, astrogliosis and cavity formation. during the different time-phase of inflammation,
[32]
Previous studies have demonstrated that application of or how necroptotic cells influence the phenotype of
Nec-1 can be protective for SCI, but which cells undergo immune cells remain to be further investigated.
necroptosis is unknown. [33,34] Our recent studies
demonstrated that RIP3 and phosphorylated MLKL are Recently, several studies showed that RIP1 and RIP3
up-regulated in reactive astrocytes and microglia after might also be involved in inflammation independent
SCI. [35,36] Reactive astrocytes, which line the spinal of necroptosis. For example, Inflammasome
[41]
cavity, die by M1 microglia/macrophage induced activation and release of IL-1 in smac-mimetic treated
necroptosis partially through toll like receptor/myeloid macrophages or in caspase-8 deficient dendrite cells
differentiation 88 signalling. Microglia, the major are dependent on RIP3, suggesting a cell-death
[35]
[42]
player of chronic inflammation post-SCI, die through independent role of RIP3 in inflammasome activation.
endoplasmic reticulum stress involved necroptosis. This should be considered when evaluating results.
[36]
These researches raised the straightforward question Combined results from MLKL deficient cells or
of how necroptosis regulateschronic inflammation mice may be helpful for clarifying the point. In view
after SCI. of the importance of necroptosis and its roles in
inflammation, better understanding of the interaction
Multiple sclerosis is another neurodegenerative between necroptosis and inflammation will be helpful
diseases characterized by demyelization and chronic for treatment of inflammatory diseases.
inflammation. The link between inflammation and
demyelination has long been recognized. A recent Acknowledgments
study from Prof. Jun-Ying Yuan’s group reported that The authors thank Dr. Hong Fan for his critical
TNF-α induces the death of oligodendrocytes in a proofreading of the manuscript and suggestions for
[37]
RIP1/3 dependent manner. In the mouse model revision.
of Gaucher’s disease, systemic TNF-α and IL-1β are
elevated, and RIP3 is up-regulated in microglia and Financial support and sponsorship
neurons. RIP3 knockout can significantly ameliorate This work was supported by National Natural Science
the development of disease and prolong the survival Foundation of China to Dr. Ya-Zhou Wang (grant code:
[38]
of animals. Amyotrophic lateral sclerosis (ALS) 81571224).
is the most adult onset motor neuron degenerative
disease, in which inflammation is the most striking Conflicts of interest
hallmark of pathological changes. Recently, it has There are no conflicts of interest.
been demonstrated that in the spinal cord of the ALS REFERENCES
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