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Zheng et al. Neuroimmunol Neuroinflammation 2019;6:1 I http://dx.doi.org/10.20517/2347-8659.2018.52 Page 5 of 12

[40]
for 12-48 h . High-mobility group box 1 protein (HMGB1) is a nuclear factor and potent pro-inflammatory
[41]
mediator, and expressed by Iba1-positive microglia . HMGB1 increases in the cerebrospinal fluid (CSF) of
SAH patients with a poor functional outcome. The upregulation of HMGB1 correlates significantly with IL-
6, IL-8, and TNF-α expression in CSF, developing towards a pro-inflammatory response after SAH [42-44] . While
another study suggests no correlation between HMGB1 and IL-6 concentrations in plasma, which may
[45]
indicate the acute activation of HMGB1 occurs only in the CNS .

MICROGLIAL M2 POLARIZATION
Although M2 microglia play a critical role in tissue repair and toxicity clearance in the other CNS
diseases [46,47] , M2-directed polarization in SAH has been less studied than M1 phenotype.

All M2a, b and c phenotypes are considered as anti-inflammatory repair M2 microglial cells. The subtypes
are generally classified by the different profiles of pro-inflammatory cytokines. M2a activation is considered
to be IL4Rα-dependent and follows exposure to IL-4 or IL-13. M2a microglia play a role in the cell repair
and regeneration by expressing anti-inflammatory and immune-regulatory molecules. M2b and M2c
microglia are largely phagocytic. M2b microglia, in particular, express high levels of IL-10 and low levels of
IL-12, whereas, M2c is characterized by high TGF-β expression [28-30,48] . M2d, distinguished from the above
subtypes of M2 polarization, results from the classically activated status through the activation of adenosine
[48]
A receptors in activated M1 pro-inflammatory cells .
2A
Upregulation of the M2-associated markers Arg1, CD163 and CD206 are observed in experimental SAH. The
[11]
expression of the markers increases slowly and peaks at 48-72 h . The mRNAs encoding IL-4, IL-10, and
[33]
TGF-β, show corresponding increments along with M2 polarization in SAH . IL-4 is an important anti-
inflammatory cytokine and instrumented in M2-like microglial responses leading to improved functional
recovery in ischemic stroke and in intracerebral hemorrhage (ICH) as well [15,30,37,49] .

Peroxisome proliferator-activated receptor-γ (PPARγ) is a superfamily of nuclear receptors with the
antioxidant and anti-inflammatory properties. Treatment with PPARγ agonists has beneficial effects on
SAH, reportedly due in part to reduced microglial activation and reduced pro-inflammatory cytokine
expression [50,51] . PPARγ is considered as an important mediator in pro-inflammatory reaction toward M2-like
microglial phenotype.

TNF stimulated gene-6 (TSG-6), a multifunctional glycoprotein, acts as a protective regulator against
inflammation. The endogenous TSG-6 is mainly expressed in microglia with the peak release in 12-24 h after
SAH injury. TSG-6 is considered as an endogenous inhibitor in pro-inflammation progression and induced
M2-like polarization. The rh-TSG-6 treated SAH rats show improved neurobehavioral outcomes and reduced
brain edema. The decreased M1 polarization and elevated M2 phenotype are observed with the remarkable
[11]
downregulation of TNF-α and upregulation of IL-10 in SAH rats .

The activation of microglia to an M1 phenotype appears mainly in the acute phase after SAH and M2
microglial activation occurs in the subacute and delayed phase. The similar theme of microglial activation
[52]
is observed in ICH . However, microglia demonstrate the M2-dominated activation in early phase in
ischemic stroke and gradually transforms to the M1 phenotype in peri-infarct regions. The ischemic neurons
[25]
lead microglial polarization toward M1 phenotype . The discrepant responses of microglia to the brain
injuries largely depend on the different pathophysiological processes. Hemorrhagic stroke triggers an acute
pro-inflammatory response mainly in proximity to the bleeding. The delayed ischemia occurred in one-third
[53]
of SAH patients . The ischemic neurons may critically contribute to the delayed M2 polarization and the
protective M2 phenotype may involve blood clearance and tissue repair in reaction.