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Page 80 Tanaka. Neuroimmunol Neuroinflammation 2020;7:73-91 I http://dx.doi.org/10.20517/2347-8659.2020.04
[71]
[70]
abundant DAMPs, such as HMGB1 and peroxiredoxin , which are potential ligands for toll-like
receptors (TLRs). DAMPs cause proinflammatory activation of microglia as lipopolysaccharide (LPS).
However, expression of proinflammatory cytokine by both microglia and macrophages in the ischemic
[72]
brain is not very remarkable . TLR ligands strongly induce expression of inducible nitric oxide synthase
(iNOS) by microglia in culture. However, microglia in the ischemic brain either do not express iNOS
protein or do so very faintly. TGFβ1 expression increases gradually until 7 days after the ischemic insults.
Either LPS or DAMPs induce phosphorylation of IkB kinase (IKK), causing degradation of IkB, enabling
the major proinflammatory transcription factor NFkB to translocate into nuclei and resulting in increased
[73]
transcription of mRNA for proinflammatory mediators . However, after being incubated with TGFβ1 for
~24 h, primary cultured microglia do not respond to LPS treatments, even when the TGFβ1 is removed
from the culture media. The TGFβ1-treated microglia cannot be classified into M2 polarized cells as they
do not express M2 markers. TGFβ1 also inhibits phosphorylation of signal transducers and activators of
transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF1), both of which augment
proinflammatory reactions of microglia in a sustained manner. When injected into the parenchyma of
the ischemic brain, both microglia and macrophages lose their immunoreactivity to phosphorylated IKK
(pIKK). Expression of other anti-inflammatory cytokines, such as IL-4, IL-10, or IL-13, is much weaker
than is that of TGFβ1. These findings indicate that TGFβ1 is a key ameliorating factor released by both
microglia and macrophages.

Roles of macrophages
Macrophages accumulate densely in the core of the ischemic and traumatic lesions where almost all
microglia disappear [11,12,19,74] . Therefore, macrophages play central roles in the immunological modulation
[74]
of pathophysiological processes in these lesions. As most of the accumulated macrophages express NG2 ,
+
[11]
they have been called brain Iba1 /NG2 cells (BINCs) . At least some are involved in removing degenerated
+
materials in the core. The macrophage-precursor monocytes invade inflamed brain tissues in ischemic
and traumatic injuries through recognizing chemokines that are typically either CCL2 or monocyte
[22]
chemoattractant protein 1 and either CX3CL1 or fractalkine . Kinetic study in the rat tMCAO models
showed that expression of CCL2 and CX3CL1 disappeared rapidly after tMCAO, within 2 days. When
macrophage proliferation was inhibited by a single administration of the anti-cancer drug 5-fluorouracil
48 h after tMCAO, accumulation of macrophages at 7 dpr did not occur . Therefore, proliferation of
[12]
monocytes that infiltrate within 2 days of the onset of the events causes the massive accumulation of
macrophages in the core of the lesion . The reduction in number of the accumulated macrophages often
[11]
causes death of the model rats. When BINCs were isolated from ischemic rat brains and transplanted into
the core lesions of other stroke model rats, the BINCs proliferate hugely and the outcomes were ameliorated
greatly. BINCs express various neuroprotective factors, such as IGF-1 and HGF, that may contribute to
improved outcomes. Although BINCs were also found in lesions in aged human brains of stroke cases,
[12]
however, the density was considerably less than that in the young rat model lesions . This may be one
reason why human stroke cases become more severe than do the young rat models. Overall, the collective
effects of macrophages on ischemic brains appear to be ameliorative.

However, the effects of monocyte-derived macrophages may not be favorable during the acute phase.
Microglia and macrophages were isolated individually from TBI model rats at 1.5 days after injury using
[10]
a fluorescence-activated cell sorter based on the different levels of CD45 expression . In this TBI model,
oxidative injury may play a significant detrimental role in inducing neuronal degeneration, as an oxidative
product 8-hydroxydeoxyguaine (8-OHdG) was found in neuronal nuclei. Reactive oxygen species (ROS) is
[75]
the cause for this product, and most of the ROS may be derived from the mitochondria of macrophages .
Infiltrating macrophages produce much higher levels of mitochondrial ROS than do microglia. ROS is also
produced by NADPH oxidase activity, and macrophages express much higher levels of NADPH oxidase
than do microglia. Moreover, expression of IL-1β and iNOS is more significant in macrophages than in