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Page 4 of 14 Choi et al. Neuroimmunol Neuroinflammation 2018;5:42 I http://dx.doi.org/10.20517/2347-8659.2018.47

[22]
from the periphery by the same chemokines that increase permeability of the blood-brain-barrier . As a
result, while microglia will always be present in brain tissue regardless of inflammatory status, peripheral
[22]
macrophages should only be present in significant numbers during periods of inflammation .
While embryological studies clearly reveal that these two populations have distinct origins, the phenotypic
differences between microglia and macrophages have often been overlooked. During recruitment of
[23]
peripheral monocytes under inflammatory conditions in both the neonatal and adult brain, Ling showed
that peripheral monocytes have the potential to histologically differentiate into microglia-appearing
cells within the CNS. This finding perpetuated the notion that circulating blood monocytes could act
[24]
as microglial progenitors that replenished microglial populations . It should be stressed that because
these original findings were based on histological morphology, the conclusions drawn on their functional
differences were limited; moreover, using histologic structural characteristics on microscopy to differentiate
microglia and macrophages is unreliable since both cell types have morphologies that are plastic and
inconsistent [25,26] . These older studies also could not take advantage of the results from more recent bulk-
RNA sequencing studies, which have since elucidated specific cellular markers for microglia, such as
low
low
CD45 , major histocompatibility complex II (MHCII) , transmembrane protein 119, P2Y purinoceptor 12,
IBA1, and Sal-like protein 1 [Figure 1B] [27-29] . Similarly, macrophages have their own specific cellular markers,
including CD45 , MHCII , CD49d, CD206, and MER receptor tyrosine kinase (MERTK) [Figure 1C] [30-35] .
hi
hi
Beyond cellular markers, microglia have characteristics that are functionally distinct from macrophages.
While microglia are considered the resident immune cells of the CNS and perform roles similar to
macrophages including phagocytosis and antigen presentation, they are also thought to have additional roles
in homeostasis such as secretion of neurotrophic factors that are essential for both normal maintenance and
[36]
response to pathological conditions . As a key component to normal parenchymal surveillance, microglia
are mobile within their own distinct territories and completely scan the brain parenchyma several times a
[37]
day . While scanning, microglia are sensitive to ATP, potassium, and purinoceptor inhibitors, and as such
can detect neuronal cell death or other pathological features with high acuity [38,39] . Upon activation, they
convert to an amoeboid phenotype and act similarly to macrophages with a high metabolic rate, rapidly
[40]
migrating to the source lesion and secreting IL-6, IL-1β, and TNFα before phagocytosing as needed .
Of note, while tissue-specific macrophages can be found in other organs outside of the CNS, microglia are
special in part due to the brain’s privileged status behind the blood-brain barrier (BBB); after embryonic
migration, they remain and exert their effect only in their original tissue with minimal interaction with
[41]
other systems . This is in contrast to other tissue-specific macrophages, like Langerhans cells, which
are epidermal-specific macrophages that have the capacity to migrate to peripheral lymph nodes upon
[19]
activation , or intestinal macrophages, which act locally but rely less upon self-renewal and more upon
[42]
recruitment of circulating macrophages to maintain their numbers .
In the context of this review however, the strongest rationale for viewing microglia and macrophages as
distinct populations emanates from their functional differences in the context of the TME, specifically in
that of GBM. In the CNS, mild or moderate inflammation leads to the protective function of microglia
as outlined above and features minimal interaction with peripheral macrophages. However, more
intense acute injury or chronic inflammatory states - as experienced in GBM - can lead to neurotoxic
and tumor-promoting activation of microglia, recruitment of peripheral macrophages, and subsequent
[41]
immunosuppression . More specifically, chemokines released in the TME attract peripherally derived
macrophages, which then migrate into the brain through the BBB and express anti-inflammatory cytokines
that attenuate the recruitment and aggregation of pro-inflammatory leukocytes (e.g., additional microglia
[35]
or neutrophils) . The complexity of the GBM TME with this consequent anti-inflammatory attenuation
[43]
ultimately contributes to pathology and promotes gliomagenesis .