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Page 8 of 12 Zheng et al. Neuroimmunol Neuroinflammation 2019;6:1 I http://dx.doi.org/10.20517/2347-8659.2018.52

[16]
MAPK signaling and improves neurological outcomes and reduces cerebral edema after SAH .

TRANSITION BETWEEN M1 AND M2
[70]
The M2 to M1 shift is observed in models of traumatic brain injury and ischemic stroke . However,
[14]
whether this transition is a result of phenotypic transformation of a single microglial population, or of the
M2 microglial migration and infiltration remains to be determined.

In the SAH model, inhibition of mammalian target of rapamycin (mTOR) can induce a shift of microglia
polarizing from M1 to M2 phenotype, as indicated by the reduction of the CD16: CD206 ratio. The shift is
along with the decrease in the levels of TNF-α and IL-1β, apoptosis and neuronal degeneration index, brain
[9]
water content and albumin extravasation in the cerebral cortex after SAH .
As described above, in the endovascular punctured SAH model, endogenous TSG-6 transforms the SAH-
driven M1 polarization to a skewed M2 polarization and balances the M1/M2 ratio to a beneficial phenotype
low
+
in the group of CD11b CD45 labeled microglia. Deficiency of endogenous TSG-6 results in a conversion to
pro-inflammatory microglial activation. TSG-6 is a promising candidate to modulate microglial polarization
[11]
for the neuroprotective effects .

INTERACTION WITH OTHER CELLS
CX3C motif chemokine ligand 1 is expressed on neurons and its receptor CX3C chemokine receptor 1, is
[71]
highly expressed on microglia . Neuronal apoptosis is mediated in a TLR4-MyD88, mTOR and HMGB1
related microglial manner [9,10,62] . Activation of mGluR5 reduces the terminal deoxynucleotidyl transferase
dUTP nick end labeling-positive cells and active caspase-3/NeuN-positive neurons in the cortex at 24 h after
[17]
SAH . The neuronal apoptosis is initiated from 24 h and increases up to two weeks after SAH [32,72,73] .

Adenosine triphosphate (ATP) is a pivotal signaling molecule regulating the interactions among different
cell types in the CNS and a high concentration of ATP induces microglial activation. Microglia extend the
processes toward the site of injection of ATP without cell body movement. This response can be inhibited
by blocking G protein-coupled purinergic receptors and connexin channels, which are highly expressed in
astrocytes. The extracellular ATP released from the damaged tissue and surrounding astrocytes trigger the
rapid chemotactic response of microglia towards injury. This provides evidence of the interaction between
[18]
microglia and astrocyte in CNS injury .
Erythrocyte extravasation is a potential danger factor to the EBI, as heme, released from injured red blood
cells, contributes to the pathogenesis of SAH. Heme is metabolized by heme oxygenase-1 (HO-1), which is
minimally expressed in the uncompromised brain, but largely upregulated in microglia following injury.
Expression of HO-1 in microglia is necessary to attenuate neuronal cell death, vasospasm, impaired
[74]
cognitive function, and clearance of cerebral blood burden .

CLINICAL IMPLICATION
Microglial responses affect neuronal survival and contribute to poor outcome after SAH. Therapeutic
intervention or suppression of unfavorable microglial response may accelerate the recovery. Several
therapeutic strategies have been implicated to prevent the detrimental effects of microglia and attenuate the
neurological impairments in preclinical studies. The application of rosuvastatin markedly inhibits microglia
activation and therefore reduces cortical apoptosis, brain edema, and improve the neuronal function
after SAH. Heparin reduces the microglial activation and reduces its production of pro-inflammation
cytokines [75,76] . As discussed above, administration of resveratrol, apigenin, melatonin, and rh-TSG-6 may