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Liu et al. Necroptosis and immune dysfunction in ALS

necroptotic pathway with the involvement of RIPK3, While the glial cell-mediated neurotoxicity is relatively
and mixed lineage kinase domain-like protein (MLKL). well documented, elucidating how other immune cells
Taken together, it appears that necroptosis plays a are involved in regulation of glial cell function and MN
critical role in connecting certain gene mutations with death remains a challenging project. First, the immune
the development of ALS. regulation in ALS appears to be more complicated than
our understanding for it on the basis of the knowledge
While necroptosis itself results in MN loss directly, acquired from other conditions. For examples, it has
it also activates the immune system and results been well known that NF-κB is a factor that mediated
[45]
in a secondary inflammatory response. We think the signals of most inflammatory factors. TNF-α, a
that inflammation/immune responses subsequently classical inflammatory cytokine that activates NF-κB
amplify MN degeneration. During this process, the and significantly increased in ALS mice and patients.
innate immune responses may act as the first line TNF-α is one of the best known factors mediating
of reactions to clean up the debris of dead cells with necroptosis, [17,18,46] but knockout of TNF-α in SOD1 G93A
[47]
the involvement of vascular reaction, infiltration of mice did not block ALS disease in SOD1 G93A mice.
neutrophil and macrophage, as well as the pro- In contrast, inhibition of NF-κB can slow down disease
[47]
inflammatory cytokine production. Later, the adaptive progression, suggesting that other inflammatory
immune components (T and B cells) get involved in cytokines, other than TNF-α, might also activate NF-
after certain MN-derived antigens (not clearly defined κB and contribute to MN death. Second, the transgenic
thus far) are processed and presented to T cells. This animal model of ALS is our current major tool to study
notion is supported by our recent finding of the roles of this disease. However, findings in animal model may
necroptosis in autoimmune bone marrow failure. We not be applicable for patient. For example, inhibition
found that necroptosis of a small portion of stem cell/ of microglial activation with Minocycline significantly
progenitors with gene mutation resulted in autoimmune delayed the onset of motor neuron degeneration and
[48]
responses, which caused a rapid depletion of bone slowed down disease progression in ALS mice,
[49]
marrow cells, which could be prevented by blocking its effect in ALS patients remains in question.
necroptotic pathway via deletion of rip3. We Furthermore, the mutual inhibitory effect among
[35]
speculate that similar roles of necroptosis may also immune components, such as the counteracting
functions between Th17 and Treg cells, as well as
exist in ALS: a small portion MN that die of necroptosis between Th1 and Th2 cells (this topic will be further
may cause the autoimmune responses, in which the discussed in the below section of ENVIRONMENT-
MN-specific antigens are released and presented to DEPENDENT FUNCTION OF CD4 T CELLS IN
+
CD4 T cells. These T cells may preferentially develop ALS), make it more complicated to use a general
+
into pro-inflammatory subsets and further amplify the immunosuppressant to achieve therapeutic effect. For
inflammation/immune responses, and cause more MN example, Sulindac, a nonsteroidal anti-inflammatory
death. Below, we continue discussing the dysfunction drug (NSAID) and inhibitor of pro-inflammatory COX-
of immune system that has been identified in ALS. 1 & COX-2, significantly increases the survival, and
preservation of spinal cord motoneurons. However,
[50]
IMMUNE DYSFUNCTION IN ALS a large number of immunosuppressive approaches,
such as cyclosporine, cyclophosphamide, and total
In the past few decades, accumulating evidence lymphoid removal failed to benefit ALS patients. [51,52]
indicates that immune system abnormalities and The previously published data for both beneficial and
inflammation contribute to the development of ALS. detrimental effects of immune components imply that
[36]
Macrophage, T cell, and mast cell infiltration have immune system has dual roles in ALS.
been observed in ALS CNS tissues. Because of
[37]
the large amount of inflammatory cells infiltrating the NECROPTOSIS AND IMMUNE DYSFUNCTION
CNS during disease progression, it was postulated
that, similar to MS, ALS may also be in part an Recently, Re et al. [32] and Ito et al. [34] found that
autoimmune disease. [38,39] Several anti-inflammatory necroptosis may be involved in the MN death. This
and/or immuno-compromising drugs also support finding provides an important connection between
the contribution of inflammatory components in the neurodegeneration and previously observed
pathogenesis of ALS. While the gene mutation and abnormal inflammation/immune response in ALS.
the resultant protein in MN may mediate a direct toxic Unlike apoptosis that does not elicit immune
effect for neuron, dysfunctional microglial cells and responses, necroptosis results in the releases of MN-
astrocytes with gene mutations may also contribute to specific antigens (MN-Ag) and other pro-inflammatory
neuronal death. [40-44] stimuli, which are also called Damage-Associated
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ June 16, 2017 111