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Liu et al. Neuroinflammation in ischemic stroke

chemokines and other proinflammatory mediators. [102] limited to the peri-infarcted area, as TGF-β can inhibit
In a pathological condition, IL-1β also connects with apoptosis but not necrosis. [113]
the activation and proliferation of astrocytes and
microglia. After Ischemic stroke, the microglia will be IL-4
activated, the M1 phenotype of microglia can express IL-4, its congener of IL-13, a product of select immune
IL-1β which act as a proinflammatory cytokines to play cells that has highly polyfunctional properties. IL-4 is
neurotoxic effect. In addition, IL-1β can prime the known to regulate a variety of immune and inflammatory
[62]
endothelium for increased leukocyte adherence and responses, including T cell differentiation and IgE class
edema formation. [103] At supraphysiological levels IL-1β in B cells. [114] IL-4 is primary produced by TH2 cells. [115]
can be neurotoxic, however, IL-1β can also promote During CD4+ cellular activation, cytokines are through
astrocytes to secrete survival promoting factors. [104] IL- T cell receptor mediated signaling and co-stimulation.
1β when bound to its cognate receptor the IL-1 receptor For instance, IL-4 mediated activation of the signal
(IL-1R) can also result in IL-1R-dependent increase in transducer and activator of transcription 6 plays an
NF-κB pathways. However, if the levels of IL-1β are important role during TH2 cell differentiation. [116] IL-4
increased above a specific threshold, it can result in have an unique properties as it polarizes macrophages/
the increase of greater amounts of the IL-1 receptor microglia toward the M2 phenotype which is anti-
antagonist (IL-1Ra). It is this balance between IL-1β inflammatory phenotype. [117] M2 macrophages/
and its antagonist the IL-1Ra that is more important microglia expresses anti-inflammatory mediators and
for its global effect and role than just the IL-1β itself. [105] give out various neurotrophic factors that aid in the
Thus, we predict that balance of IL-1β and IL-1Ra resolution of inflammation via increased trophic input
might be good predictor for patient outcome following and the augmentation of phagocytosis and proteolysis
ischemic stroke. However, few clinical studies have of dead, diseased cells/proteins, ultimately paving the
made use of their level as stroke biomarkers. IL-1β way for tissue repair. [118] Consequently, IL-4 may have
levels mostly were associated with poor long-term a neuroprotective function to promote tissue repair and
functional outcome in study, [106] while IL-1Ra levels may act as a therapeutic factor.
have shown to be predictive of the development of
post-stroke infections. [107] STROKE-ASSOCIATED INFECTION AND
NEUROINFLAMMATION
Transforming growth factor beta
Transforming growth factor beta (TGF-β) proteins are Infection frequently occurs in both and after stroke
multifunctional cytokines with pleiotropic functions. [108] that can induce immune and neuroinflammatory
TGF-β can regulate various biological processes, responses. [119-122] The characteristics of post-stroke
including hematopoiesis, angiogenesis, cell infections include immune suppression, elevation
proliferation, differentiation, migration and apoptosis. of IL-6, decreases in TNF-α levels and inflammation
TGF-β also plays an important role in the regulation of are among the factors. Along with stroke-associated
the immune system. TGF-β is a superfamily, including infection, inflammatory responses are the defense
inhibins, activins, growth differentiation factors mechanism against infection and it can also be a
(GDFS), bone morphogenetic proteins (BMPs), TGF-β pathogenic mechanism that precipitates stroke and
isoforms, and glial cell derived factors. [109] The main neurological sequelae. [123] It is generally recognized
research object is TGF-β isoforms. TGF-β exists in at that stroke-associated infection may be a source of
least three isoforms: TGF-β1, TGF-β2, and TGF-β3. [110] inflammation and autoimmunity as infection facilitates
In the TGF-β superfamily, only TGF-β1, produced the maturation of APCs into potent immunostimulatory
by activated microglia, and TGF-β2, produced by cells. [124] Stroke-associated infection is mostly induced
astrocytes and neurons. [111] TGF-β1 and TGF-β2 by virus. [125-127] Virus enters the CNS through two
increased prominently after ischemic stroke. After pathways: (1) hematogenous dissemination through
Ischemic stroke, TGF-β produced by activated M2 BBB; [125] (2) neuronal retrograde dissemination. [126] It
phenotype macrophage, plays an anti-inflammatory also suggested that virus can replicate in macrophage
role and contributes to recovery after brain injury. and CCR5+ T cells in the CNS. [127]
[63]
TGF-β reduces microglial activation and thus reduces
the potential harmful effects associated with activated CONCLUSION
microglia. TGF-β decreases the expression of other
poisonous cytokines and suppresses the release of The role of neuroinflammation in ischemic stroke
oxygen and nitrogen derived products. TGF-β can has drawn increasing attention. In this review, we
also stimulate the release of IL-1Ra and promote summarize the relevance of inflammation in the nervous
angiogenesis. [112] Its protective effects, however, are system and introduce the neuroinflammatory cells
162 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ August 28, 2017