Post-Ischemic Inflammation in the Brain

Abstract

Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In this review, we focus on the post-ischemic inflammation triggered by infiltrating immune cells, macrophages, and T lymphocytes. Brain ischemia is a sterile organ, but injury-induced inflammation is mostly dependent on Toll-like receptor (TLR) 2 and TLR4. Some endogenous TLR ligands, high mobility group box 1 (HMGB1) and peroxiredoxin family proteins, in particular, are implicated in the activation and inflammatory cytokine expression in infiltrating macrophages. Following macrophage activation, T lymphocytes infiltrate the ischemic brain and regulate the delayed phase inflammation. IL-17-producing γδT lymphocytes induced by IL-23 from macrophages promote ischemic brain injury, whereas regulatory T lymphocytes suppress the function of inflammatory mediators. A deeper understanding of the inflammatory mechanisms of infiltrating immune cells may lead to the development of novel neuroprotective therapies.

Full text

REVIEW ARTICLE
published: 31 May 2012
doi: 10.3389/fimmu.2012.00132
Post-ischemic inflammation in the brain
Takashi Shichita1,2 , Ryota Sakaguchi 1,3, Mayu Suzuki 1,3 and AkihikoYoshimura1,3 *
1Department of Microbiology and Immunology, School of Medicine, Keio University,Tokyo, Japan
2Department of Research Promotion, Precursory Research for Embryonic Science and Technology, Tokyo, Japan
3Core Research for Evolutional Science and Technology, Japan Science andTechnology Agency,Tokyo, Japan
Edited by:
Masaaki Murakami, Osaka University,
Japan
Reviewed by:
Daisuke Kamimura, Osaka University,
Japan
Yasunobu Arima, Osaka University,
Japan
*Correspondence:
Akihiko Yoshimura, Department of
Microbiology and Immunology,
School of Medicine, Keio University,
35 Shinanomachi, Shinjuku-ku,Tokyo
160-8582, Japan.
e-mail: yoshimura@a6.keio.jp
Post-ischemic inflammation is an essential step in the progression of brain
ischemia-reperfusion injury. In this review, we focus on the post-ischemic inflammation
triggered by infiltrating immune cells, macrophages, and T lymphocytes. Brain ischemia is
a sterile organ, but injury-induced inflammation is mostly dependent on Toll-like receptor
(TLR) 2 andTLR4. Some endogenousTLR ligands, high mobility group box 1 (HMGB1) and
peroxiredoxin family proteins, in particular, are implicated in the activation and inflamma-
tory cytokine expression in infiltrating macrophages. Following macrophage activation, T
lymphocytes infiltrate the ischemic brain and regulate the delayed phase inflammation. IL-
17-producing γδT lymphocytes induced by IL-23 from macrophages promote ischemic brain
injury, whereas regulatory T lymphocytes suppress the function of inflammatory media-
tors. A deeper understanding of the inflammatory mechanisms of infiltrating immune cells
may lead to the development of novel neuroprotective therapies.
Keywords: cytokine, inflammation, ischemia, brain, stroke,T cells, macrophages, DAMPs
INTRODUCTION
Stroke is a leading cause of death and disability worldwide. The
most common type of stroke is ischemic stroke (e.g., approxi-
mately 70% of strokes in Japan are ischemic). However, intra-
venous administration of tissue plasminogen activator (tPA) is
the only globally approved treatment for ischemic stroke, and it
is a time-dependent therapy that must be provided within 4.5 h
after stroke onset. Thus, there is a need for an efficacious therapy
that can be administered beyond this time window,one that targets
neuroprotection rather than clot dissolution (Lo, 2010;Moskowitz
et al., 2010).
Brain infarction is tissue death caused by ischemia due to
severe stenosis or occlusion of a cerebral artery. Ischemic brain
tissue is deprived of oxygen, glucose, and lipids, and eventually
becomes necrotic. Brain inflammation occurs in this necrotic
brain tissue, following the breakdown of the blood-brain barrier
(BBB) and infiltration of blood immune cells. Infiltrating immune
cells promote ischemic brain inflammation by producing vari-
ous inflammatory mediators, and also clear away necrotic debris.
After the demolition of necrotic debris has been completed, brain
inflammation subsides.
Despite intensive studies, the complexity of the brain inflam-
mation mechanism has thus far prevented sufficient clarification
(Eltzschig and Eckle, 2011;Iadecola and Anrather, 2011;Macrez
et al., 2011). Macrophages and neutrophils are pivotal players in
the various processes of brain inflammation, but the mechanism of
their activation is still unknown. In addition, T or B lymphocytes
have been also reported to participate in delayed brain inflam-
mation. This review focuses on the mechanism of ischemic brain
inflammation triggered and sustained by infiltrating immune cells.
POST-ISCHEMIC INFLAMMATION IN THE EARLY PHASE OF
BRAIN ISCHEMIA
Severe ischemia induces hypoxia and glucose deprivation in brain
tissue. Calcium and sodium ions are stored within brain cells and
glutamate is released into the extracellular compartment. The pro-
duction of reactive oxygen species (ROS) activates platelets and
endothelial cells, leading to microvascular occlusion. Oxidative
stress reduces the beneficial effects of nitric oxide (NO), a potent
vasodilator and inhibitor of platelet aggregation and leukocyte
adhesion, in endothelial cells. Oxidative stress and the inflam-
matory cascade alter the permeability of the BBB. The activation
of matrix metalloproteinases (MMPs) and the expression of var-
ious other proteases lead to BBB breakdown which exacerbates
leukocyte extravasation. Intravascular leukocytes firmly adhere to
activated endothelium by the interaction of endothelial expres-
sion of intercellular adhesion molecule-1 (ICAM-1) and leukocyte
β2 integrins (Iadecola and Anrather, 2011). The infiltration of
leukocytes is enhanced by BBB breakdown and by chemokines.
Brain cells, including astrocytes, oligodendrocytes, endothe-
lium, and pericytes, constitute a neurovascular network, which
is essential for metabolic requirement of neurons (Iadecola, 2004;
Fraser, 2011). These brain cells also contribute to triggering post-
ischemic inflammation by producing inflammatory mediators.
TNF-α,IL-1β, NOS (nitric oxide synthetase), and MMPs which
enhance cerebrovascular permeability and exaggerate brain edema
(Takano et al., 2009;Morancho et al., 2010). Thus, Infiltrat-
ing leukocytes and injured brain cells produce various inflam-
matory mediators, leading to the beginning of post-ischemic
inflammation (Barone and Feuerstein, 1999;Figure 1).
INNATE INFLAMMATORY CYTOKINES AND INFLAMMATORY
MEDIATORS
Various cytokines and mediators are produced from infiltrating
immune cells and brain cells as a result of ischemic changes of
brain. IL-1βis expressed in ischemic brain tissue within 30 min
after stroke onset. IL-1βdirectly induces apoptosis of neuronal
cells and enhances the expression of chemokine (RANTES, etc.)
in microglia and astrocytes. IL-1βis considered to be a neurotoxic
mediator,given that the loss of IL-1βfunction is reported to reduce
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Shichita et al. Mechanisms of cerebral post-ischemic inflammation
FIGURE1|Post-ischemic inflammation in the brain.Within 24h after
ischemic stroke onset, various inflammatory mediators are expressed in
ischemic brain tissue. ICAM-1 promotes leukocytes infiltration. Cytokines
activate infiltrating leukocytes and directly induce ischemic injury in brain
cells. Matrix metalloproteinases (MMPs) alter the permeability of epithelial
cells and are implicated in BBB breakdown. Endogenous TLR ligands
(DAMPs) are released from necrotic brain cells and activate infiltrating
immune cells. These inflammatory mediators trigger post-ischemic
inflammation by infiltrating leukocytes.There are currently few effective
therapies for this phase of leukocyte infiltration.
infarct size (Boutin et al., 2001). IL-1βis produced in an inactivate
form, pro-IL-1β, which is cleaved by caspase-1 to become an active
17 kDa form. Recently, the mechanism of IL-1βproduction and
caspase-1 activation mediated by inflammasome has been the sub-
ject of particular attention. Inflammasome has been shown to be
present in neurons, astrocytes, microglia, and macrophages in the
ischemic brain (Abulafia et al., 2009;Chakraborty et al., 2010).
Several types of inflammasome have been discovered, denoted
NALP1, NALP3, AIM, and so on, but the particular type most
important in ischemic brain injury remains unknown. Hypoxia
or ATP is reported to activate inflammasome,which then activates
caspase-1 and induces IL-1βproduction (Martinon et al., 2002).
In addition, IL-1βis mostly produced from monocytes which are
activated by endogenous Toll-like receptor (TLR) ligands, given
that IL-1βmRNA level in infiltrating mononuclear cells is drasti-
cally reduced in TLR2/4-double deficient mice after ischemic brain
injury.
TNF-αis another important mediator implicated in the pathol-
ogy of the ischemic brain. TNF-αis expressed in ischemic brain
tissue within 1 h after stroke onset, and upregulation of the TNF
receptors is observed thereafter. TNF-αexercises neurotoxic effects
by inducing apoptotic neuronal cell death and enhancing MHC
class II and ICAM-1 expression in astrocytes, leading to leukocyte
infiltration and BBB breakdown. TNF-αgene knockout (KO) mice
or anti-TNF-αneutralizing antibody administration has been
shown to reduce infarct volume, compared with that in control
mice. However, TNFR KO mice, which lack both p75 and p50
genes, exhibit enlargement of infarct volume on day 1 following
ischemic brain injury, indicating that TNF-αcan be considered
to function as both a neurotoxic and a neuroprotective mediator
(Hallenbeck, 2002). It appears that the opposing functions, toxic
or protective, depends on the type of brain cell involved. TNF-α
promotes post-ischemic inflammation but also participates in a
negative feedback loop to suppress inflammatory signal cascades,
and it controls the duration of post-ischemic inflammation by
regulating these two functions.
IL-6 is also expressed in ischemic brain tissue, but ischemic
brain damage is not attenuated in IL-6 KO mice or in anti-IL-
6R antagonistic antibody-treated mice (Yamashita et al., 2005).
However, it has been recently reported that IL-6 produced from
brain cells contributes to neoangiogenesis and neuronal sur-
vival through STAT3 activation (Jung et al., 2011;Gertz et al.,
2012). Consistent with this, the inhibition of JAK/STAT path-
way or the enhanced role of SOCS3 (negative regulator of
JAK/STAT pathway) has been reported to promote neuronal
cell death (Yadav et al., 2005;Yamashita et al., 2005). Thus, it
is possible that IL-6 protects neuron from cell death, although
a significant role of IL-6 in brain ischemia has not yet been
established.
Matrix metalloproteinases are essential neurotoxic mediators
that promote BBB breakdown and post-ischemic inflammation.
Functionally similar to IL-1β, MMPs induce apoptotic neuronal
cell death by TNF-αand FasL processing. The neurotoxic func-
tion of MMP-9 is particularly established, given that infarct size
is reduced in MMP-9-deficient mice compared to that in con-
trol mice (Asahi et al., 2000). Intercellular adhesion molecule-1
(ICAM-1) is another neurotoxic mediator. The increased expres-
sion of ICAM-1 observed in cerebrovascular endothelial cells is
implicated in the promotion of leukocyte infiltration. ICAM-
1-deficient mice reveal attenuated ischemic damage and the
administration of anti-ICAM-1 antibody decreases the number
of infiltrating immune cells (Connolly et al., 1996;Liesz et al.,
2011).
Chemokines are also important enhancers of post-ischemic
inflammation. Chemokines (RANTES, MCP-1, IL-8, etc.) have
been reported to promote leukocyte infiltration into the ischemic
brain (Terao et al., 2008, 2009;Strecker et al., 2011). Although
the chemokines for lymphocyte infiltration remain unknown,
CCL12, CCL20, and their receptor,CCR6, are essential for the exac-
erbation of experimental autoimmune encephalomyelitis (EAE;
Martin et al., 2009;Reboldi et al., 2009). Whether these lympho-
cyte chemokines also function in acute organ injury, such as brain
ischemia, should be elucidated in the future.
Sphingosine-1-phosphate (S1P) is a bioactive phospholipid.
At sites of tissue injury, S1P is mainly released from platelets
and mediates its effect via activation of cell-surface S1P recep-
tors, which are ubiquitously expressed in brain cells (Dev et al.,
2008). S1P receptors are also present on the surface of T lym-
phocytes; therefore, S1P has been thought to play an essential
role in T lymphocyte infiltration of inflammatory tissue. Recently,
the therapeutic effect of FTY720 (fingolimod), a functional S1P
receptor antagonist, has attracted attention. The administration of
FTY720 has been shown to attenuate ischemic brain damage and
decrease the number of infiltrating T lymphocytes in the ischemic
brain (Shichita et al., 2009;Hasegawa et al., 2010). Furthermore,
S1P receptors are expressed in neurons,astrocytes, and microglial
cells. S1P acts on these cells directly and exerts effects that include
astrocyte proliferation and migration, oligodendrocyte differenti-
ation and cell survival, and neurite outgrowth and neurogenesis
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Shichita et al. Mechanisms of cerebral post-ischemic inflammation
(Dev et al., 2008). Thus, S1P is considered to be an important
inflammatory mediator in the ischemic brain.
ROLE OF TLR
Leukocyte infiltration is an essential step in the progression of
post-ischemic inflammation. However, the mechanisms that acti-
vate these infiltrating immune cells, macrophages, and lympho-
cytes, are not yet fully clarified. TLRs are an essential type of
receptor for innate and non-specific immune response to general
pathogens such as bacteria, viruses, and so on. The demonstration
that TLR2 and TLR4 are pivotal for sterile organ injury,including
ischemic brain injury, has recently attracted attention (Chen et al.,
2007;Tang et al., 2007).
Toll-like receptors are expressed on both leukocytes and brain
cells, although whether the effect of TLRs on brain cells is
neurotoxic or neuroprotective remains unclear. TLR stimulation
in macrophages and lymphocytes induces strong and various
inflammatory responses. In ischemic brain injury, post-ischemic
inflammation and subsequent ischemic damage depend on TLR2
and TLR4, but not TLR9 (Tang et al., 2007;Hyakkoku et al.,
2010). TLR2- or TLR4-deficient mice demonstrate both signifi-
cant reduction of infarct volume and suppression of neurotoxic
inflammatory responses. Analysis of bone marrow chimeric mice
indicates that TLRs in infiltrated immune cells, but not in residen-
tial microglia, have a neurotoxic effect on ischemic brain injury
(Yang et al., 2011). In addition, mice lacking MyD88, the adaptor
protein under almost all TLR signaling cascades other than TLR3,
are reported to show no improvement of ischemic brain injury
(Famakin et al., 2011). These results indicate that the function of
TLRs may be dependent on kind of cells in brain.
Toll-like receptor-2 or TLR4 deficiency suppresses inflamma-
tory cytokine expression in infiltrating immune cells on day
1 after brain ischemia (Shichita et al., 2012). Although both
TLR2 and TLR4 signaling cascades are essential triggers for post-
ischemic inflammation, and activators of infiltrating immune
cells, the particular molecules that activate TLR2 and TLR4 in
the ischemic brain remain unclear. Because the brain is a sterile
organ, pathogens derived from bacteria or viruses are completely
lacking in the normal and ischemic brain. This indicates that
certain endogenous molecules released from necrotic brain cells
become TLR stimulators, and several endogenous molecules have
indeed been reported to activate TLR signaling cascades. Such
endogenous molecules are called danger associated molecular pat-
terns (DAMPs), and are considered to be danger signals or alarm
molecules that warn immune cells of tissue and cellular injury.
DAMPs IN INJURED BRAIN
Several molecules in the brain have been reported as DAMPs.
Heat shock proteins (HSPs),β-amyloid (Aβ), hyaluronan, heparin
sulfate, DNA or RNA immune complex, oxidized low-density
lipoproteins (oxLDL),and others, can stimulate TLRs (Marsh et al.,
2009;Rivest, 2009;Yanai et al., 2009;Stewart et al., 2010;Zhang
et al., 2010). However, it remains unclear which molecule is the
most important for triggering post-ischemic inflammation and
inflammatory cytokine expression.
High mobility group box 1 (HMGB1) is a well-elucidated
DAMP and is also implicated in ischemic brain injury (Kim et al.,
2006;Liu et al., 2007;Hayakawa et al., 2010). HMGB1 increases
vascular permeability and promotes BBB breakdown (Zhang et al.,
2011). HMGB1, which is localized in cell nuclei in the normal
brain, translocates into the cytosolic compartment and is released
into the extracellular compartment in the ischemic condition.
The administration of anti-HMGB1-neutralizing antibody pro-
tects the BBB and reduces infarct volume. Thus, HMGB1 is an
essential DAMP in ischemic brain injury. Extracellular release of
HMGB1 is observed within 6 h after stroke onset, but is dimin-
ished by 12 h after the onset (Qiu et al., 2008;Zhang et al., 2011).
Thereafter, the infiltration of immune cells and the production
of inflammatory cytokines become evident. This indicates that
HMGB1 may not directly activate infiltrating immune cells in the
ischemic brain.
We have identified the peroxiredoxin (Prx) family proteins as
strong inducers of inflammatory cytokines in infiltrating immune
cells (Shichita et al., 2012). Prx family proteins are known to
exert a protective effect by catalyzing ROS. In the ischemic brain,
the expression of Prx within brain cells is increased by ischemic
stress, and such intracellular Prx is thought to be neuroprotective
(Patenaude et al., 2005;Rashidian et al., 2009;Figure 2). How-
ever, as necrosis occurs, this Prx is released into the extracellular
compartment where they induce inflammatory cytokine expres-
sion in infiltrating immune cells by stimulating TLR2 and TLR4
(Figure 2). It is interesting to note that the Prx family proteins
have a common active region for TLR activation and are extracel-
lularly released over 12h after stroke onset, which coincides with
the timing of leukocyte infiltration. Thus, Prx has two opposing
functions, one inside, and one outside, brain cells. Furthermore,
there is a time lag as well as functional differences between HMGB1
and Prx (Figure 3).
T LYMPHOCYTES IN ISCHEMIC BRAIN INJURY
It has been recently suggested that T lymphocytes play a role as
mediators in the delayed phase of brain ischemia (Yilmaz et al.,
2006). The number of infiltrating T lymphocytes in ischemic brain
tissue increases over 24h after stroke onset and reaches its peak
in the delayed phase (around day 3; Schroeter et al., 1994;Jan-
der et al., 1995). Infiltrating T lymphocytes appear to be localized
FIGURE 2 |Two opposing functions of Prx, one inside, and one outside,
brain cells. Ischemic stress increases Prx expression within brain cells,
which contributes to their survival by catabolizing reactive oxygen species
(ROS). When ischemic phenomena finally result in necrosis, the Prx
released from necrotic brain cells into the extracellular compartment then
functions as a strong TLR2 and TLR4 stimulator (DAMP) for the infiltrating
macrophages in ischemic brain tissue.
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Shichita et al. Mechanisms of cerebral post-ischemic inflammation
FIGURE3|Post-ischemic inflammation triggered by DAMPs and
infiltrating immune cells. At the hyperacute phase of brain ischemia
(within 6 h after stroke onset), HMGB1 is released from brain cells and
induces BBB breakdown. Following this, blood cells begin to infiltrate into
ischemic brain tissue via disrupted vessels during the acute phase of
ischemia (12–24h after stroke onset). Prx is extracellularly released from
necrotic brain cells and activates infiltrating macrophages via TLR2 and
TLR4. Activated macrophages produce inflammatory cytokines (IL-23, IL-1β,
TNF-α, etc.) which promote ischemic brain injury. At the delayed phase of
brain ischemia (more than 24h after stroke onset), IL-23 induces IL-17
production from γδT lymphocytes, which further enhances ischemic
damage. Thus, HMGB1 is a hyperacute DAMP, while Prx is secondarily
active in post-ischemic inflammation, during the acute phase.
to the infarct boundary zones, typically close to blood vessels.
By Percoll gradient centrifugation, infiltrating immune cells have
been analyzed (Shichita et al., 2009). The number of infiltrating
immune cells reaches the peak at day 3 after stroke onset and most
of these are macrophages. Approximately 1 ∼1.5% of immune
cells are T lymphocytes which are consisted of 30 ∼40% CD4+
helper T lymphocytes, 20 ∼30% γδT lymphocytes, and 20∼30%
CD8+cytotoxic T lymphocytes. Inflammatory cytokines, IL-1β,
TNF-α, IL-23, and IL-12 have been shown to be produced from
macrophage and play important roles in promoting brain injury.
However, role of various cytokines from T lymphocytes, such as
IFNγand IL-17 in ischemic brain injury has not been clarified.
Although the function of these infiltrating T lymphocytes in
the ischemic brain is not yet clear, T lymphocytes, on the whole,
are considered to act as a neurotoxic effector. This is indicated
by the fact that severe combined immunodeficient (SCID) mice,
and recombination activating gene (RAG)-deficient mice,both of
which lack T and B lymphocytes, reveal significant reduction of
infarct volume (Yilmaz et al., 2006;Hurn et al., 2007). In addi-
tion, the depletion of CD4+(helper) or CD8+(cytotoxic) T
lymphocytes, but not one of the B lymphocytes, is reported to
attenuate ischemic brain damage. There is a report that regulatory
B lymphocytes protect brain from ischemic damages; however, the
neurotoxic effect of lymphocytes is considered to be majorly made
byTlymphocytes(Ren et al., 2011). It will be important to eluci-
date which subtype of lymphocytes is implicated in ischemic brain
injury (see T Lymphocyte Cytokines in Ischemic Brain Injury).
It is not yet clear whether a specific antigen in the brain is
involved in the activation of these infiltrating T lymphocytes.
Up to now, it has been thought likely that these T lymphocytes
mediate antigen-independent, innate inflammatory responses,
because post-ischemic inflammatory responses have been shown
to be driven by the innate immune system. However,some reports
suggest the importance of antigen recognition by T lymphocytes
in ischemic brain injury. Treatment with T cell receptor (TCR) lig-
ands, which are major histocompatibility complex (MHC) class II
molecules bound to myelin peptides, is protective against ischemic
brain injury (Subramanian et al., 2009). Infarct size in myelin basic
protein (MBP) tolerized animals has been shown to be reduced
compared to that in control mice. Thus, there is a possibility that
some T lymphocyte subsets specifically tolerized to brain proteins
could be protective to ischemic brain injury (Becker et al., 2003;
Becker, 2009). This idea is supported by the recent finding that
regulatory T lymphocytes are protective to ischemic brain injury
(Liesz et al., 2009).
T LYMPHOCYTE CYTOKINES IN ISCHEMIC BRAIN INJURY
T lymphocytes are considered to mediate ischemic brain injury
by producing various cytokines, and IFN-γand IL-4 are well-
known classical examples. In ischemic injury, IFN-γis thought
to be neurotoxic, as it acts on neurons directly and induces
apoptotic neuronal cell death in vitro (Lambertsen et al., 2004).
However, a protective effect by the IFN-γdeficiency has not been
observed, and the role of IFN-γin ischemic brain injury is con-
troversial (Lambertsen et al., 2004;Yilmaz et al., 2006). IL-12
is produced from myeloid cells such as macrophages, dendritic
cells, neutrophils, and so on, and is important for the differenti-
ation of IFN-γ-producing helper T lymphocytes (Th1). IL-12 is
expressed in ischemic brain tissue by infiltrating immune cells, but
its function has not been fully elucidated.
IL-4 may have the potential to attenuate ischemic damage and
promote tissue repair, since IL-4-deficient mice demonstrate exac-
erbated ischemic damage and neurological deficit (Xiong et al.,
2011). Although the emerging recognition of the function of IL-4
for tissue repair has recently attracted attention, whether or not
IL-4 is directly implicated in tissue repair in ischemic brain injury
is still unclear (Chen et al., 2012).
IL-10 is an immunosuppressive cytokine and is thought to
have a neuroprotective effect in ischemic brain injury. IL-10 is
produced from regulatory T lymphocytes (Treg) and suppresses
the neurotoxic function of TNF-αand IFN-γ(Liesz et al., 2009).
The overexpression of IL-10 by an adenovirus vector protects hip-
pocampal neurons against apoptotic cell death (Ooboshi et al.,
2006).
IL-17 is an emerging therapeutic target for various organ
injuries. IL-23 has been reported to be essential for IL-17 induc-
tion from T lymphocytes, and to play a critical role in EAE
(Cua et al., 2003). In ischemic brain injury, IL-23 is produced
by infiltrating macrophages on day 1, and it induces IL-17 pro-
duction from γδT lymphocytes in the delayed phase (Figure 3).
Both IL-23 KO mice and IL-17 KO mice show significantly atten-
uated ischemic brain damage on day 4. The IL-17 receptor is
ubiquitously expressed in brain cells and modifies various inflam-
matory responses in the central nervous system. IL-17 has been
reported to promote the expression of inflammatory cytokines
and chemokines from macrophages (Fossiez et al., 1996). IL-17
also modulates the epithelial barrier function by promoting MMPs
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Shichita et al. Mechanisms of cerebral post-ischemic inflammation
and ICAM-1 expression (Kebir et al., 2007;Ifergan et al., 2008).
Although it remains unknown whether IL-17 directly affects
neurons, IL-17 is thought to be a promising therapeutic tar-
get for suppressing post-ischemic inflammation. Thus, IL-23-
induced IL-17-producing γδT lymphocytes play a pivotal role
in the delayed phase of brain ischemia (Figure 4). IL-17 pro-
duction from γδT lymphocytes requires only IL-1βand IL-23
stimulation, but not specific TCR stimulation,and IL-6 and TGFβ
stimulation are indispensable for IL-17-producing helper T lym-
phocyte (Th17) differentiation (Sutton et al., 2009). Thus, it is
reasonable that γδT lymphocytes mediate ischemic brain injury,
given that γδT lymphocytes produce IL-17 more rapidly than
does Th17.
THE POSSIBILITY OF MEDICAL INTERVENTION IN
POST-ISCHEMIC INFLAMMATION
Post-ischemic inflammation in the brain is considered to have two
opposing functions in stroke patients; one beneficial, the other
harmful. Post-ischemic inflammation promotes brain swelling
(brain edema) which leads to the compression of normal brain
tissue surrounding the ischemic core and the exacerbation of neu-
rological deficits. This undesirable effect of post-ischemic brain
inflammation should be suppressed by medical intervention when
possible. However, post-ischemic inflammation is also thought to
promote tissue repair in the recovery phase of ischemic stroke.
Thus, suppression of all inflammatory responses in ischemic
brain tissue is not always effective, due to their involvement
in both ischemic injury and tissue repair processes. To create
novel neuroprotective strategy, it may be possible to control
the balance between the neurotoxic and neuroprotective effects
of post-ischemic inflammation by targeting specific inflamma-
tory mediators. For example, therapy which both suppresses the
FIGURE4|Schematic model of IL-23/IL-17 inflammatory pathway in
ischemic brain tissue. Infiltrating macrophages produce IL-23 and IL-12,
which induce IL-17-producing γδT lymphocytes and IFN-γ-producing helperT
lymphocytes (Th1), respectively. IL-17 from γδT lymphocytes acts on
macrophages and brain cells directly, and promotes the expression of
inflammatory mediators that enhance apoptotic neuronal cell death and
BBB breakdown.
inflammatory subset of T lymphocytes (e.g., IL-17-producing γδT
lymphocytes) and promotes Treg function may be desirable.
It is possible that administration of γδTCR-depleting anti-
body or anti-IL-12/IL-23p40 antibody [p40 is a common sub-
unit of the IL-12 heterodimer (p35/p40) and IL-23 heterodimer
(p19/p40)] will become a therapeutic tool for ischemic stroke (Shi-
chita et al., 2009;Konoeda et al., 2010). Thus, neuroprotective
therapies for ischemic brain injury may be developed by targeting
the IL-23/IL-17 inflammatory pathway. Furthermore, one of the
most advantageous points of therapy targeting IL-17-producing
T lymphocytes is its long therapeutic time window. Since current
globally approved therapy is limited to intravenous administration
of tPA,which should be performed within 4.5 h after stroke onset,
further elucidation of the inflammatory mechanisms of the T lym-
phocytes that infiltrate the ischemic brain during the 24-h-period
after stroke onset is needed.
FTY720 is one of the most promising therapeutic tools for
ischemic stroke at this time (Wei et al., 2011). FTY720 decreases
the number of infiltrating T lymphocytes, including γδT lympho-
cytes. The most troublesome side effect of FTY720 administration
is the increased incidence of bacterial pneumonia after stroke
(Meisel and Meisel, 2011). It is possible that FTY720 interferes
with peripheral lymphocyte distribution in the body after stroke
and thus inhibits the protective function of peripheral T lympho-
cytes against bacterial infection. Although it has been reported that
FTY720 does not promote spontaneous bacterial infection after
experimental stroke in mice, future studies aimed at developing
effective clinical interventions for stroke patients should seek to
minimize this kind of detrimental effect of FTY720 (Pfeilschifter
et al., 2011).
In conclusion, research has gradually shed light on the mech-
anisms of post-ischemic inflammation. A deeper understanding
of these intricacies in the context of medical intervention should
enable the development of novel neuroprotective strategies that
are more effective and have a longer therapeutic time window
(Figure 5).
FIGURE 5 | Strategy for developing neuroprotective therapy by
suppressing neurotoxic inflammatory response.The targeting of specific
inflammatory mediators from macrophages and T lymphocytes can
attenuate neurotoxic inflammatory reactions.
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Shichita et al. Mechanisms of cerebral post-ischemic inflammation
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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential con-
flict of interest.
Received: 14 April 2012; paper pend-
ing published: 30 April 2012; accepted:
08 May 2012; published online: 31 May
2012.
Citation: Shichita T, Sakaguchi R,
Suzuki M and Yoshimura A (2012)
Post-ischemic inflammation in the
brain. Front. Immun. 3:132. doi:
10.3389/fimmu.2012.00132
This article was submitted to Frontiers in
Inflammation, a specialty of Frontiers in
Immunology.
Copyright © 2012 Shichita, Sakaguchi,
Suzuki and Yoshimura. This is an open-
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