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Liu et al. Necroptosis and immune dysfunction in ALS

Molecular Patterns (DAMPs), such as mitochondria, in ALS was due to the defect of CD4 T cells with
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ATP and alarmins. [46] In addition, Frakes et al. SOD1 G93A mutation or due to the special cytokine
[45]
found that NF-κB-activation determines the pro- microenvironment in SOD1 G93A mice, we isolated
inflammatory phenotype of microglial cells, which in CD4 T cells in the spleen from WT and SOD1 G93A
+
turn contributes to neuronal death. Two questions mice and adoptively transferred to immune-deficient
concerning how immune cells are involved in mice Rag2 (“normal” microenvironment) or SOD1 G93A
-/-
the regulation of glial cell function remains to be (inflammatory environment) and studied if they can
answered. First, what are the specific autoimmune support motoneuron survival after facial nerve axotomy
cells involved in the interaction of glial cell and MN? (FNA). Facial motoneuron (FMN) survival post 4-week
and second, how should we dissect the dual functions operation in each group were counted and calculated
of immune system in ALS? As aforementioned, the as percentage of FMN number on axotomized side
general immunosuppressants, which have inhibitory compared to uninjured side. Rag2 mice lacks B and
-/-
effects on overall immune system, appear to have T cells and FNA induced a significant FMN loss, which
minimal therapeutic effect, presumably due to the could be prevented by adoptive transfer of either WT
simultaneous inhibition of immune components that whole splenocytes or purified CD4 T cell. SOD1 G93A
+
have beneficial effects. [51,52] Consistent with this mice also showed a significant FMN loss than WT
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notion, knockout of CD4 T cells in SOD1 G93A mice mice after FNA. However, such loss could only be
resulted in exacerbation of ALS-like symptoms and rescued by WT whole splenocytes but not purified
a decreased life span. [53,54] Collectively, it appears WT CD4 T cells, suggesting that microenvironment
+
that CD4 T cell-mediated regulation determines the determines the beneficial function of CD4 T cells and
+
+
direction and nature of immune responses in ALS, that microenrivronment in SOD1 G93A mouse does not
and an ideal immune-based therapy for ALS should support the development of beneficial CD4 T subsets.
+
be able to inhibit the “detrimental” effects of immune Therefore, we compared the FNA-induced FMN loss
cell without simultaneously comprising the “beneficial” between Rag2 mice that received SOD1 G93A whole
-/-
functions. Therefore, it is necessary to identify the splenocytes and Rag2 mice that received purified
-/-
specific subsets of immune cells and to elucidate how SOD1 G93A CD4 T cells. As expected, we found that the
+
they are involved in the pathogenesis of ALS. purified SOD1 G93A CD4 T cells still could support FMN
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survival but whole splenocytes did not. Collectively,
[58]
ENVIRONMENT-DEPENDENT FUNCTION OF these data suggest that microenvironment in SOD1 G93A
CD4 T CELLS IN ALS mice might have a condition that primes CD4 T cell
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into detrimental subsets.
In ALS patients, it was found that the total number of
lymphocyte and naïve CD4 T cells (CD45RA ) was TH17 CELLS, NERVE INJURY AND ALS
+
+
decreased in late-stage and there was a significant
+
CD4 T cell infiltration in the spinal cord and brain. Th17 cells are a subset of CD4 T cells that play an
+
In addition, T cells were present in ALS patient important role in promoting inflammation, including
cerebrospinal fluid with a predominant Th1 phenotype. angiogenesis and the recruitment of multiple types
CD4 T cells have different subsets with distinct of immune cells to injury sites. Th17 cells are
+
[59]
functions, which are determined by the cytokines they crucial for the development of certain autoimmune
produce. IFN-γ-producing Th1 and IL-17-producing diseases, exhibiting neurodestructive effects in
Th17 (both produce TNF-α) promote inflammation; In neuroinflammatory diseases. In ALS patients,
[60]
contrast, IL-4 producing Th2 and IL-10-producing T elevated IL-17 and Th17-related cytokines (IL-6,
regulatory cell (Treg) inhibit inflammation. Other and TNF-α, IL-1 and IL-23) [61-63] have been observed.
our groups have showed that CD4 T cells mediate However, the contribution of Th17 cells in promoting
+
anti-inflammatory effect after nerve injury as well as ALS development has not been established yet
in ALS disease; however it is in context- and subset- because of two challenges: late diagnosis and
dependent manner. [53-56] It is generally thought that chronic disease. Late diagnosis makes it difficult to
beneficial effects of CD4 T cells are mainly mediated conclude whether the abnormal immune responses/
+
by its anti-neuroinflammatory subsets, such as Treg inflammation is the cause or result of the disease. The
and Th2 cells [56,57] and that detrimental effects are chronic nature of ALS makes it difficult to determine
mediated by pro-inflammatory CD4 T subsets, such the best timing for the detection of such autoimmune
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asTh1 and Th17 cells. The differential development responses. To resolve these two challenges, we have
of CD4 T subset is determined by both CD4 T applied motor nerve injury (facial nerve axotomy, FNA)
+
+
cells and their cytokine environment. To determine into a pre-symptomatic mouse ALS model (8-week old
whether the “detrimental” Th cells development SOD1 G93A ) mice, which introduces nerve injury and
112 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ June 16, 2017