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Tanaka. Neuroimmunol Neuroinflammation 2020;7:73-91 I http://dx.doi.org/10.20517/2347-8659.2020.04 Page 79

basic fibroblast growth factor (bFGF) is reduced considerably, whereas expression of pro-apoptotic factors,
such as Bid, Bad, and Bax, is increased, leading to marked loss of the hippocampal neurons. These findings
indicate that microglia contribute significantly to supporting neuronal survival.

RESPONSE OF MICROGLIA AND MACROPHAGES IN THE BRAIN WITH ISCHEMIC AND
TRAUMATIC INJURIES THAT CAUSE BBB BREAKDOWN
Severe damage to brains and spinal cords disrupts the BBB, resulting in massive infiltration of blood-
borne cells, such as monocytes and neutrophils [9,22] . Discrimination of the roles of these immune cell types
[10]
in pathophysiological processes is becoming possible, although further study is necessary . Different
responses of microglia and macrophages are seen in the ischemic lesion core and the ischemic penumbra
or peri-ischemic region [11,27] . It should be noted that microglia are very vulnerable to various kinds of severe
[64]
brain insults, including CO intoxication, as mentioned above . Six hours after reperfusion in tMCAO
(90 min-occlusion) in a rat model of severe stroke, microglia undergo apoptotic degeneration in the lesion
core, whereas neurons appear unchanged [9,11] . Therefore, blood-borne macrophages and neutrophils are
the main immune cells in the lesion cores and during the acute phase. However, microglia are both viable
and become activated in the peri-region neighboring the core of the lesion and modulate pathological
processes.

Roles of microglia
The activated microglia in the peri-ischemic regions bear large phagosomes that can be recognized by
immunohistochemical staining of CD68 . Moreover, they frequently express NG2 chondroitin sulfate
[27]
[27]
proteoglycan (NG2), which may be another marker for phagocytosing microglia and macrophages .
[47]
+
CD68 -phagocytosing microglia in the SNr and GPi in the rat PD model brains also express NG2 .
+
+
Such NG2 /CD68 microglia engage in phagocytosis of degenerating neurons in the very limited region
located along the border zone delineating the ischemic core and the penumbra . The region is termed
[27]
[65]
the demarcation zone and is characterized by high expression of NG2. Neurodegeneration, known
as delayed neuronal death, is still progressing in the zone in the subacute phase, which has long been a
therapeutic target in stroke research to ameliorate the outcome of stroke.
Microglia are assumed to eliminate still viable neurons via phagocytosis in the ischemic penumbra [66,67] .
Because of decreased blood flow, neurons reduce their ATP synthesis and, thus, frequently externalize
phosphatidylserine (PS) on their surface. PS is a typical eat-me-signal molecule that is recognized by
molecules, such as either Milk fat globule EGF-like factor 8 (MFG-E8) or protein S, which are, in turn,
recognized by either vitronectin receptor or Mer receptor tyrosine kinase (MerTK) expressed by microglia.
Expression of MFG-E8 and MerTK is enhanced either in activated microglia or in macrophages in the
ischemic lesions. Knocking out expression of MerTK or MFG-E8 by microglia prevented the delayed
neuronal loss considerably. These findings may indicate that CD68 /NG2 -phagocytosing microglia are
+
+
aggravating cells in stroke pathology.
Administration of the CSF1R antagonist PLX3397 to mice depletes microglia. This pharmacological
intervention was used to study the overall effects of microglia on the outcome of ischemic brain insults.
Eliminating microglia increases infarct volume, indicating that the overall effects of microglia on the
ischemic brain are ameliorative. Microglia in the non-ischemic regions may maintain the neuronal
circuitry, suppress proinflammatory activation of astrocytes, and prevent infiltration by various leukocytes,
such as T cells, monocytes, and granulocytes [68,69] .

Activated microglia in the ischemic brain release a considerable quantity of transforming growth factor
[27]
β1 (TGFβ1) , which is a strong immunosuppressive cytokine. Ischemic brain lesions should contain