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Page 268 Yoshimura et al. Neuroimmunol Neuroinflammation 2020;7:264-76 I http://dx.doi.org/10.20517/2347-8659.2020.22

macrophages originate during the acute phase of inflammation after stroke model [14,20] , the contribution of
microglia to severe inflammation post stroke is not very clear. Depletion of microglia leads to aggravated
neuronal damage and apoptosis after ischemic brain injury, suggesting that microglia plays an important
[44]
role in neuroprotection . Mechanistically, microglia senses damaged cells through the purinergic
receptors (P2X4R, P2X6R, P2X12R) which respond to adenosine triphosphate released from dead cells.
The activation of the purinergic receptors initiates neuroprotective responses rather than destructive
inflammation through the recruitment of microglia to the point of injury [45,46] . Microglia also express
clearance receptors such as Msr1, complement receptors, and receptors for apoptotic cells [32,47] . A recent
study shows beneficial effects of repopulating microglia which support adult neurogenesis by augmenting
[48]
the survival of newborn neurons in traumatic brain injury thorough IL-6 trans-signaling pathways . IGF-1
[49]
produced by microglia has been found to be neuroprotective . However, the significance of IGF-1 in
neuroinflammation and neuroprotectin remain controversial .
[50]
ROLE OF LYMPHOCYTES IN POST-ISCHEMIC BRAIN INFLAMMATION
It has been reported that lymphocytes including T cells and B cells play various roles in the pathophy-
[51]
siology of stroke . B cells and immunoglobulins are detected within and around the stroke core in
a subgroup of stroke and dementia patients, and also in a murine experimental stroke model. Several
studies suggest that post-stroke cognitive impairment has been associated with B cell activation and auto-
antibody production . Nevertheless, the specific roles of B cells and/or antibodies in neurological deficits
[52]
[53]
and inflammation after ischemic brain injury remain uncertain . Plasma cells in the central nervous
system (CNS) of mice with EAE have been shown to originate in the gut and produce IgA, which confers
[54]
resistance to mice to the effector stage of EAE through the production of IL-10 . Interestingly, stroke
patients demonstrate a type of auto-immunoreactivity to brain antigens .
[55]
T cells have been more intensively investigated than B cells. This is mostly because various cytokines, such
+
as IL-10, IL-17, IL-21, IFN-γ, and TNF-α produced from CD4 T cells and/or γδT cells, affect and regulate
glial cells, endothelial cells, neural cells, and various immune cells [56,57] . IL-21 is predominantly produced
+
from CD4 T cells, but the role of this particular cytokine in stroke is controversial. In mice, a locus on
distal chromosome 7 has been described to contribute variations in post-ischemic cerebral infarct volume,
and the IL-21 receptor has been identified as a strong candidate which functions in a neuroprotective
manner . However, another study suggested that IL-21 promotes brain injury after stroke in mice , thus
[58]
[57]
further research is necessary to clarify the role of IL-21 in brain injury.
The route of infiltration of T cells to the brain is not described clearly. A recent study shows that T cells
specifically accumulate within the peri-infarct cortex after stroke and that the ipsilateral choroid plexus
[59]
plays a key cerebral invasion route for T cells . This study suggests that the CCR2-ligand gradient between
cortex and choroid plexus serves as the potential driving force for T cell invasion.

In the experimental cerebral ischemia model, infiltration of subsets of T cells occurs at various time
points [Figures 1 and 2]. Many reports indicate that T cells promote brain damage at the early phase of
stroke [19,60] . In humans, FTY720 (fingolimod) treatment within 72 h post stroke onset blocks the infiltration
[61]
of pathogenic T cells into the brain, effectively ameliorating neurological symptoms in the patient .
CD8 T cells may infiltrate within several hours after stroke onset . Nerve-damaging substances such as
[61]
+
[62]
+
granzymes and perforin from CD8 T cells can exacerbate the infarction . γδT cells increase immediately
after stroke onset and are present in the brain parenchyma accompanied with BBB breakdown. On day
3 after stroke onset, the number of γδT cells reaches its maximum concentrations [19,21] . IL-17 produced
from γδT cells promotes neural cell damages in the ischemic penumbra region [19,21,63] . Taken together, γδT
cells depletion well as anti-IL-17 neutralizing antibody are shown to suppress ischemic brain injury [19,64] .
+
[65]
CD4 T cells and NKT cells infiltrate the brain after 24 h of ischemic stroke . These reports indicate that