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Liu et al. Neuroinflammation in ischemic stroke

histocompatibility complex class II molecules and ROLES OF CYTOKINES IN CEREBRAL
cytokines. [74-76] Following activation of microglia, the ISCHEMIA
release of pro-inflammatory mediators from these
microglia favor the permeability of the BBB. Together IFN-γ
with the secretion of chemokines, this promotes the IFN is a type cytokines that plays a key role in the
successive entry of systemic leukocytes including immune system. The IFN family cytokines are divided
neutrophils, macrophages and lymphocytes, which into two types. Type I IFNs constitute by a largest
share several functional features with microglia. [77,78] IFN class and comprise the IFN-α, -β, -ε, -κ, and
-ω, type that share notable sequence homology and
Microglia is the resident macrophage of the brain are produced by most cell types. IFN-γ is a unique
and a key modulator of immunologic responses member of the type II IFN. [93,94] IFN-γ is principally
after ischemic stroke. Under normal conditions, secreted by monocytes, macrophages, T cells, natural
microglia is primarily involved in activity-dependent killer (NK) cells, dendritic cells and B lymphocytes.
synaptic pruning and repair. [37] When ischemic IFN-γ is a critical regulator of immune function and
stroke occurs, the native microglia undergoes provides a robust first-line of defense against invading
morphological transformation from a ramified resting pathogens. Additionally, IFN-γ has plenty of biological
state in preparation for the forthcoming immune functions including regulation of several aspects
response. [79,80] Once reperfusion beginning, microglia of the immune responses, stimulation of antigen
come to be activated to an active, characterized by presentation via upregulating class I and class II
many branching processes in the penumbra, motile major histocompatibility complex (MHC) molecules on
amoeboid state. [81] These activated microglia start the surface of macrophages and T cells. IFN-γ when
to engulf endothelial cells via phagocytosis, which bound to its cognate receptor can activate a variety
allows the entrance of blood serum components. [82] of downstream signaling pathways, particularly the
Active microglia phagocytoses foreign organisms as Janus kinase (JAK)/signal transducer and activator of
well as injured brain cells. [60,83] In ischemic stroke, transcription (STAT). [95,96] All of these characteristics
activation of microglia is the early stages of the potentially influence the process of atherogenesis.
neuroinflammation process even within minutes. [83-85] Numerous lines of evidence have indicated that IFN-γ
Several reports have demonstrated that defective is highly expressed in atherosclerotic lesions and
microglial activation increased the infarction and believed to have a critical role in the atherogenesis.
[97]
apoptosis after ischemic stroke. [86] Stroke is the main atherosclerosis disease. Under
[98]
inflammatory conditions, MHC class II specific CD4+
Microglial activation following ischemic stroke can cells will be activated. Activated CD4+ cells easily
promote activated microglia to migrate toward the infiltrate through BBB into the CNS following cerebral
ischemic hemisphere of the cerebral cortex. [87] It is I/R. Therefore, microglia have the opportunity
[99]
suggested that active microglia have predominantly to retain and further stimulate CD4+ cells already
harmful effects in the acute stages of ischemic primed to differentiate into T helper 1 (TH1) cells
stroke and most beneficial effects appear in delayed producing proinflammatory cytokines (IL-2, IFN-γ,
stages. [62,88] Microglia morphology is changed TNF-α) or into T helper 2 (TH2) cells producing
either to M1, the typically activated phenotype, or cytokines that support antibody-mediated responses
to M2, an alternatively activated phenotype, after (IL-4, IL-5, IL-10, lL-13). [100] IFN-γ is thought to have
stroke. [61,89,90] M1 microglia activated by LPS and the a key role in the polarization of microglia. TH1 cells
pro-inflammatory cytokine interferon-gamma (IFN-γ) produces proinflammatory cytokines IFN-γ that can
shows harmful effect after stroke. [91] In contrast, M2 return to activation microglia into M1 phenotype,
phenotype microglia contribute to stroke recovery shows pro-inflammatory response, and produces pro-
through anti-inflammatory cytokines such as IL-4. [92] inflammatory cytokines and oxidative metabolites.
In ischemic stroke, the M2 phenotype is dominant in
both local microglia and newly recruited macrophages IL-1β
at earlier stages. The M1 phenotype increases IL-1β belongs to the family IL-1. IL-1β is a key
progressively in peri-infarct regions. Thus, ischemic immunoregulatory and proinflammatory cytokine
neuron induces changes towards the M2 phenotype that affects almost all cell types. IL-1β is produced
in microglia and macrophages. [62] Considering the following the formation of a inflammasome; such
opposing roles of microglia phenotypes in ischemic as monocytes and macrophage/microglia. [101] After
stroke, it is critical to develop therapeutic strategy Ischemic stroke, IL-1β can activate nuclear factor
by restraining the morphological transformation and (NF)-κB via the activation of TLRs allowing NF-κB
promoting the beneficial of microglia. to transactivate genes associated with cytokines,
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ August 28, 2017 161