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Page 10 of 14 Choi et al. Neuroimmunol Neuroinflammation 2018;5:42 I http://dx.doi.org/10.20517/2347-8659.2018.47

in peri-tumoral areas and instead resulted in a significant increase in macrophage recruitment from the
periphery and subsequent infiltration. Of key importance is that deletion of Cx3cr1 in mice saw an increase
in IL-1β production from both microglia and macrophages, implicating this receptor in the suppression of
[79]
IL-1β production .
The importance of IL-1β lies in the IL-1β/CCL2/IL-6 interaction between microglia and glioma cells [Figure 2A-C].
Specifically, IL-1β released from both microglia and macrophages activates the p38 mitogen-activated protein
kinase (MAPK) pathway in glioma cells, which in turn results in increased expression of CCL2-the agonist
[80]
for CCR2 on microglia [Table 1] . This results in an increase in microglial production of IL-6 and eventually
MMP-2, which facilitates tumor migration, invasion, and gliomagenesis [Figure 2C] [81,82] . The CX3CR1/IL-1β/
CCL2 pathway continues to be an area of active interest, particularly in regard to reduction of IL-6 pro-tumor
[80]
signaling and inhibition of MMP-based pathways in microglia [Figure 2C and D] .
Similarly, studies have examined the p38 MAPK pathway in microglia and its potential for anti-tumor ther-
apy. Minocycline, a tetracycline that inhibits the p38 MAPK pathway, appears to counteract the pro-tumor
phenotype of microglia and reduce tumor growth in vitro and in vivo by inhibiting downstream microglial
MT1-MMP expression in mouse models. Decrease in MT1-MMP expression is in turn associated with de-
creased MMP-2 activity, which follows a similar treatment schema as mentioned above in the IL-1β/CCL2/
IL-6 pathway [Figure 2C] [83,84] .

Also stimulating secretion of CCL2, IL-6, IL-1, and NO is TNFα, which is readily produced by glioma-
associated microglia [79,85] . TNF receptor 1 (TNFR1) activation leads to the degradation of IκBa, an inhibitor
of NFκB signaling. This degradation leads to a positive feedback loop with p65/p50 nuclear translocation
and subsequent transcriptional activation of TNFα [86,87] . Meanwhile, NFκB activation also activates pro-
migratory genes that contribute to tumor invasiveness involving several pro-tumor chemokines and MMP
[88]
pathways . As such, there is ongoing interest in targeting TNFR1 and the related NFκB pathway in
[86]
microglia .
Moreover, GBM cells induce TLR2/6 activation in both macrophages and microglia via the myeloid
differentiation primary response 88/TLR8 signaling pathway, which in turn leads to an increase in
[89]
metalloproteinases like MMP-9 that facilitate tumor invasion and angiogenesis [Figure 2C and D] . TLR2
on microglia is also directly involved with promoting tumor invasion with downstream production of MT1-
[90]
MMP . Studies done with murine GL261 glioma cells injected into TLR2 KO mice resulted in smaller
[90]
tumor burden and reduced MT1-MMP levels in glioma-associated microglia .

Contributing further empiric credence to the idea that macrophages and microglia are distinct populations
[91]
in the TME, Jacobs et al. found that propentofylline, a methylxanthine, directly acts only on microglia-and
not on macrophages-through tumor necrosis factor receptor superfamily, member 19 (TNFRSF19)/TROY
inhibition. In a rat glioma model, they demonstrated that TROY is upregulated in infiltrating microglia, with
downstream expression of pro-tumor genes Pyk2, Rac1, and pJNK. The potential effectiveness of targeting
TROY was shown through a series of siRNA experiments that resulted in inhibition of microglial migration
towards glioma cells and, as a result, decreased pro-tumor activity [Figure 2C].

Another important pathway involves signal transducer and activator of transcription 3 (STAT3), which
is upregulated in both GBM and glioma-associated microglia and is associated with GBM pathogenesis,
[95]
progression, and immune evasion [92-94] . A study by Lisi et al. in 2014 examined the use of rapamycin
to inhibit mTOR in glioma; the result was the reversal of pro-tumor functions in microglia with glioma-
specific cytotoxic behavior. Normally, mTOR leads to an increase in STAT3 expression, which in turn results
in increased production of pro-tumor cytokines IL-6, IL-10, CXCL2, and HIF-1α [Figure 2C-E]. With mTOR