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Page 2 of 12 Zheng et al. Neuroimmunol Neuroinflammation 2019;6:1 I http://dx.doi.org/10.20517/2347-8659.2018.52

concentrates on aneurysm repair to avoid further bleeding. Also, cerebral blood flow augmentation is needed
to reduce vasospasm. Identification of specific events enriches our understanding of the pathophysiological
processes of SAH and enhances the investigation of potential therapeutic strategies. The recent prospective
studies failing to confirm the association between vasospasm and outcomes in SAH patients attests to the
[5,6]
need to develop new therapeutic directions .

Microglia, the resident immune cells of the central nervous system (CNS), are a pivotal component of
[7,8]
neuroinflammation after SAH . Microglia respond to brain injury through altering their morphology and
polarization to activate in response to pathophysiological brain insults. Microglia are activated and M1-
dominated polarization is demonstrated in the early phase of SAH. Microglial activation contributes to the
SAH pathogenesis including brain edema, blood-brain barrier permeability, and neuronal apoptosis. The
depletion of microglia leads to a significant decrease in neuronal apoptosis in the early phase [9-11] . Microglial
activation involves numerous mediators and signaling pathways, especially the toll-like receptor 4 (TLR4).
TLR4 plays an important role in inflammatory response and neuronal death after SAH and the majority of
TLR4 is expressed by microglia. TLR4 activation in microglia results in secretion of inflammatory factors
such as tumor necrosis factor-α (TNF-α) and deletion of TLR4 significantly reduces the neuronal apoptosis
in SAH [10,12] . Increasing experimental evidence supports manipulation of microglial polarization as a strategy
for preventing disease progression and improving outcomes [13-15] .

Microglia are the primary source of cytokines and chemokines, which contribute to the immunomodulatory
signaling after SAH [11,16,17] . These molecules initiate secondary brain injury but can also participate in
the subsequent brain repair processes. Elevations in neuroinflammatory factors including monocyte
chemoattractant protein-1 and TNF-α are regarded as predictors of overall negative outcome, but not
necessarily useful predictors of vasospasm [18,19] . The anti-inflammatory factors such as interleukin-4 (IL-4),
IL-10 and transforming growth factor-β (TGF-β) are released following the acute pro-inflammatory response
[11]
in SAH .
In this review, we summarize microglial function after SAH, with a specific focus on microglial activation
and polarization. Furthermore, we discuss the potential modulators of microglial polarization and function.
The interactions of microglia with other cells are discussed as well.

MICROGLIA
Microglia derive from yolk sac primitive progenitors and migrate into the CNS in early embryogenesis.
Microglia have the capabilities of proliferation and differentiation, which are basically associated with
[8]
disease states . Microglia are highly dynamic in the resting state and activate rapidly in response to a
[20]
set of transcription factors and growth factor receptors in brain injury or degeneration conditions .
Microglial cells activate through modulating the phenotype and generating a large number of cytokines and
chemokines. Recent studies indicate that microglia have highly motile processes and continually survey the
[21]
microenvironment, even in the normal brain . Therefore, microglia represent the guardians of the brain in
various injuries and diseases.

Microglia are classically considered as CNS-resident macrophage, as they share many macrophage-associated
[22]
markers, such as CD11b . However, the lineage relationship between microglia and macrophages clearly
indicates that they are separate cell types. Microglia proliferate locally and tend to remain viable longer than
[23]
macrophage. In addition, microglia are not normally supplied by bone marrow-derived cells .
The microglial phenotype is modified in response to the brain injury. Experimental evidence indicates that
microglia dynamically and temporally polarize into a classically activated state and alternatively activated
state, which contributes to tissue damage or repair respectively [24-26] . Microglial polarization is considered