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IL-23 induce IL-17 production from infiltrated γδT cells, further promote inflammation, BBB breakdown,
and neuronal damage [19-21] . IL-17 is a cytokine which has been shown to play important pathological
roles not only in ischemic stroke, but also in various neuroinflammation including neurodegenerative
diseases [22-24] . The inflammasomes, which are necessary for mature IL-1β release, have also been described
to cause deterioration in infarct volume resulting in neural defects in stroke patients. Inhibition of
inflammasome is shown to be effective for reducing neuroinflammation and subsequently reducing infarct
volume increase [20,25] .

RESOLUTION MECHANISM OF INFLAMMATION AFTER STROKE
After 3-4 days post-ischemic stroke onset, inflammatory macrophages termed M1 type macrophages, are
converted into repairing macrophages or M2-type macrophages. Repairing macrophages play a role in
scavanging tissue debris and necrotic cells, futher supporting neural repair by releasing neurotrophic factors
[26]
including insulin growth factor (IGF)-I [Figure 2]. It has been suggested by some studies that IL-10
[27]
and TGF-β from M2-type macrophages and microglia, promoting the resolution of inflammation . Is
is not clear whether the same M1 macrophages may convert to M2 type, or M2 macrophages replace M1
type macrophages although an imaging study of infiltrated macrophages in experimental autoimmune
[28]
encephalomyelitis (EAE) model revealed that single macrophage changes its phenotype from M1 to M2 .
For clearance of DAMPs, Msr1 (macrophage scavenger receptor-1 or what is known as CD204 or SCARA1)
was identified as a major scavanger receptor [29,30] . Msr1 promoter was described to be activated by Maf-b,
and an RAR agonist, Am80, upregulating MAF-B expression, therefore promoting Msr1 expression and
clearance of DAMPs which ultimately facilitates neurological recovery . Am80 has also been shown to
[29]
[31]
be neuroprotective by activating the PI3-kinase/Akt pathway . Msr1 has been shown in several studies
to clear various neurotoxic molecules including amyloid-β thus playing an important neuroprotective
role [32,33] . Mannose receptors on infiltrating macrophages have also been reported to be involved in the
clearance of DAMPs in focal cortical ischemia .
[34]
The early activation of microglia in the post-ischemic brain was demonstrated to be neuroprotective by
2+
regulating neuronal Ca overload and spread of depolarization. Pharmacological ablation of microglia
results in infract size increase and dysregulation of neuronal circuit, while microglia repopulation reverses
[35]
these effects . The pro-resolving mediators including protectins and resolvins, which have been shown to
be neuroprotective. Resolvins reduce neural damage through suppression of leukocyte infiltration, IL-1β
[36]
expression, and NF-κB activation . Neuroprotectin-D1 similarly reduces infarct volume and diminishes
[37]
disease burden . LXA had also been reported to be neuroprotective by virtue of mitigating astrogliosis,
4
IL-1β, TNFα expression, and neutrophil infiltration. Additionally, it also converts phenotypes of monocytes
from inflammatory to an anti-inflammatory and serves functionally to repair tissues . However, the
[38]
mechanism of resolution (or suppression) of inflammation by microglia and these lipid-mediators remains
to be described.

Lack of CCR5 expression has been reported to increase the severity of ischemic brain injury . CCR5
[39]
[40]
is uniquely expressed in cortical neurons within the damaged brain . CCR5 antagonists accelerate
recovery from neurological and cognitive dysfunction. Although various roles of CCR5 in neurons have
been reported, the inhibition of CCR5 has been found to suppress astrocyte reactivity and macrophage
recruitment [40,41] . Nevertheless, another study has revealed the pathogenic role of CCR5 in cerebral
[42]
ischemia , suggesting that various types of cells may express CCR5 and contribute to both neuronal
inflammation and tissue repair of the ischemic brain.

ROLE OF MICROGLIA IN RESOLUTION OF INFLAMMATION AND NEURAL REPAIR
Microglia have been shown to play important roles in neural inflammation, resolution of inflammation
[43]
and clearance of dead cells in the brain . Since major sources of IL-1β and IL-23 is infiltrated M1 type