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Zheng et al. Neuroimmunol Neuroinflammation 2019;6:1 I http://dx.doi.org/10.20517/2347-8659.2018.52 Page 7 of 12

κB signaling pathway is more related to the M1 polarization. Based on the high-throughput sequencing
and co-expression network analysis of long non-coding RNAs (lncRNAs) and mRNAs, knockdown of
lncRNA fantom3_F730004F19 attenuates inflammation in LPS-treated BV-2 microglial cells through the
[39]
downregulation of TLR4 and CD14, with decreased TNF-α, IL-1β and IL-6 expression . Methemoglobin
(metHgb) is considered as an endogenous TLR4 ligand. The application of metHgb into the rat subarachnoid
space induces the widespread TLR4-mediated neuroinflammation resulting in the microglial activation and
[56]
TNF-α upregulation .

Substantial treatment strategies have been investigated based on targeting TLR4. Treatment with astaxanthin
significantly reduced the TLR4 activation in SAH rats. The subsequent pro-inflammatory releases of IL-
1β, TNF-α, and intercellular adhesion molecule 1 are downregulated accordingly at both the protein and
[38]
mRNA levels in vivo and in vitro . Peroxiredoxin 2 (Prx2) is a member of Prx protein family. Prx2 activates
microglia through TLR4/MyD88/NF-κB signaling pathway and the TLR4 knock-out mitigates the Prx2-
induced neuronal cytotoxicity after SAH, which suggests the critical role of Prx2 in the inflammatory
[37]
modulation responding to hemorrhage attack . Post-SAH treatment with resveratrol, a naturally occurring
polyphenolic compound with the anti-inflammatory activity, apigenin or melatonin ameliorates EBI after
SAH by suppressing the activation of the TLR4 pathway and expression of MyD88 and NF-κB. The reduced
microglia activation and inflammatory cytokines results in the mitigation of neural apoptosis, brain edema,
and neurological deficits [12,57,58] .

HMGB1 has endogenous cytokine-like activity and involves both in the EBI and delayed cerebral ischemia
[59]
after SAH by modulating the microglia-dependent pro-inflammation . Treatment with anti-HMGB1
antibody significantly reduces the expression of TLR4, IL-6, TNF-α, and iNOS and reverses the basilar artery
[35]
vasospasm in the SAH model . The application of glycyrrhizin and glycyrrhizin acid, rhinacanthin-C,
purpurogallin, and 4’-O-β-D-glucosyl-5-O-methylvisamminol attenuating the expression of HMGB1,
ameliorate inflammatory effect by downregulating M1-related cytokines [60-65] . The molecules targeting
HMGB1 may be potential candidates for the treatment of inflammatory brain injury after SAH.

Signal transducer and activator of transcription 3 (STAT3) inflammatory signaling mediates microglial
activation both in primary microglia and microglial cell lines. Increased STAT3 expression is accompanied
by the elevated expression of IL-6 rather than IL-10. The STAT3/Janus kinases (JAK) cascade is a pivotal
inflammatory signaling pathway and widely expressed in the brain maintaining [66,67] . Based on our studies
and published data, STAT3 responses to the hemorrhage attack immediately through phosphorylation and
translocation into the nuclei. STAT3/JAK pathway is activated and upregulated within 24 h after SAH with
the increased pro-inflammatory cytokines release. The mediators and inhibitors, such as erythropoietin
and AG490, suppress the STAT3/JAK pathway activation and reduce the M1-like inflammatory response
and ameliorate brain injury after SAH [68,69] . The neuroprotective effect of TSG-6 on modulating microglial
phenotype involves suppression of the STAT3/suppressor of cytokine signaling 3 pathway activation through
[11]
impeding the translocation of phosphorylated STAT3 .

Other mediators trigger the M1 classical activated status in brain in response to pro-inflammatory signals.
Activation of metabotropic glutamate receptor 5 (mGluR5) attenuates the M1 microglial activation by
downregulating both mRNA and protein expression of pro-inflammatory cytokines, including IL-1β, IL-
[17]
6, and TNF-α, at 24 h after SAH . Albumin suppresses microglial activation resulting in reduced Iba-1
and CD68 staining in the cortex on 1 day after SAH. Expression of M1 microglial markers including iNOS,
IL-1b, CD16, and CD32 are remarkably suppressed as well. The albumin induced microglial modulation is
associated with binding of albumin to a C-type lectin microglial receptor (mincle), followed by the reduction
[33]
of mincle/spleen tyrosine kinase/IL-1b signaling in ipsilateral hemisphere subjected to SAH . Peli1, an E3
ubiquitin ligase, mediates the induction of pro-inflammatory cytokines in microglia via mitogen-activated
protein kinase (MAPK) signaling pathway. Peli1 promotes the expression of M1 microglia polarization
biomarker CD16/32 and iNOS after SAH. Knockdown of Peli1 suppresses microglial activation by inhibiting