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Tanaka. Neuroimmunol Neuroinflammation 2020;7:73-91 I http://dx.doi.org/10.20517/2347-8659.2020.04 Page 81
[76]
microglia. Although NO is occasionally described as a neuroprotective factor , it can bind to superoxide
- [77]
O and form the highly toxic molecule peroxynitrite (ONOO ) . Conversely, microglia can save neurons
-
2
from degeneration induced by oxidative stress [78,79] . Collectively, the roles of blood-borne macrophages are
more detrimental than are those of microglia in the earliest phase of severe brain injuries.
Some different phenotypes of macrophages accumulate in the traumatic and ischemic lesion cores [10,19] .
During the acute phase, 2 days after the onset of stroke, most macrophages exhibit a rather neurotoxic
[10]
phenotype characterized by expression of IL-1β and iNOS and release of ROS . However, most
macrophages exhibit neuroprotective phenotypes characterized by expression of IGF-1 and HGF. This does
not imply that a single population of macrophages turns into the two different (neuroprotective and neuro-
destructive) populations depending on the pathological processes. As the neuroprotective macrophages
characteristically express NG2, they are termed BINCs. However, BINCs cannot be classified as M2-
polarized macrophages; they express a typical M1 marker CD86 and not an M2 marker CD163, whereas
+
they do not express IL-1β and iNOS in the ischemic lesion core. There is a minor subpopulation of Iba1 /
+
CD68 macrophages; though they do not express either NG2 or CD86, they express IL-1β, CCL2, and iNOS,
in addition to TLR4, which may be the source of the proinflammatory factors. Characteristically, they
express CD200 [19,80] , which mediates immunosuppressive signals primarily to myeloid cells expressing its
receptor CD200R. Though the CD200 /NG2 macrophages are likely the predominant population during
+
-
the acute phase of severe brain injury, they undergo gradual apoptotic degeneration due to the oxidative
injury, as evidenced by the accumulation of 8OHdG materials in their nuclei . Importantly, as they are
+
[10]
[19]
not proliferative, they decline in number along with the pathological processes . Alternatively, BINCs
may be a small population during the acute phase, but they are highly proliferative and become the main
macrophage population in the lesion core. Figure 2 summarizes the two types of macrophages.
In conclusion, macrophages also play both favorable and unfavorable roles in brain pathology. However,
unlike the case with microglia, there are different macrophage populations that exert favorable and
unfavorable effects independently.

PHARMACOLOGICAL INTERVENTIONS
The term “double-edged sword” has been used frequently to describe the favorable and unfavorable effects
of microglia and macrophages [81-83] . Pharmacological interventions have long been sought that would either
induce or strengthen the favorable effects of these cells [15,84] . However, in the case of macrophages, it may
be more likely that there are different subpopulations with different effects on neurons rather than there
being opposing effects of a single population of macrophages. Nevertheless, numerous pharmacological
interventions have been shown to modulate the natures of both microglia and macrophages. Some of these
are discussed below. Here it is better to once again confirm the notion that the favorable and unfavorable
phenotypes for neuronal survival are incompatible with the M1 and M2 classifications [18,19,72] .

Glucocorticoids
Glucocorticoids have strong immunosuppressive effects on many kinds of cells and may be the most
often-used anti-inflammatory agent in laboratory and clinical settings. Glucocorticoids may have stronger
anti-inflammatory effects on microglia than do adrenergic agonists, minocycline, troglitazone, and
antidepressants [Figure 3]. They cause microglial cells to shrink, reduce lysosomal enzyme activities,
and suppress proliferation of primary cultured rat microglia . They suppress expression of the
[85]
[43]
proinflammatory mediators by LPS-treated cultured microglia primarily at the transcription level .
Glucocorticoids can bind not only to the glucocorticoid receptor but also to the mineralocorticoid
[85]
receptor . Mineralocorticoid receptor may mediate activating effects on microglia rather than inhibitory
effects. As the major rodent glucocorticoid corticosterone has an affinity for both mineralocorticoid