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REVIEW ARTICLE
published: 14 October 2014
doi: 10.3389/fncel.2014.00319
Post-ischemic inflammation regulates neural damage and
protection
Takashi Shichita1,2 , Minako Ito1and Akihiko Yoshimura1*
1Department of Microbiology and Immunology, School of Medicine, Keio University,Tokyo, Japan
2Precursory Research for Embryonic Science andTechnology, Japan Science and Technology Agency, Tokyo, Japan
Edited by:
Arthur Liesz, University Hospital
Munich, Germany
Reviewed by:
Mathias Gelderblom, University
Medical Center Hamburg-Eppendorf,
Germany
Alexander Dressel, University
Medicine Greifswald, Germany
*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 important in ischemic stroke pathology. However, details
of the inflammation process, its resolution after stroke and its effect on pathology and
neural damage have not been clarified. Brain swelling, which is often fatal in ischemic
stroke patients, occurs at an early stage of stroke due to endothelial cell injury and severe
inflammation by infiltrated mononuclear cells including macrophages, neutrophils, and
lymphocytes. At early stage of inflammation, macrophages are activated by molecules
released from necrotic cells [danger-associated molecular patterns (DAMPs)], and inflam-
matory cytokines and mediators that increase ischemic brain damage by disruption of the
blood–brain barrier are released. After post-ischemic inflammation, macrophages function
as scavengers of necrotic cell and brain tissue debris. Such macrophages are also involved
in tissue repair and neural cell regeneration by producing tropic factors. The mechanisms
of inflammation resolution and conversion of inflammation to neuroprotection are largely
unknown. In this review, we summarize information accumulated recently about DAMP-
induced inflammation and the neuroprotective effects of inflammatory cells, and discuss
next generation strategies to treat ischemic stroke.
Keywords: damage-associated molecular patterns (DAMPs), inflammation, cytokines, inflammasome, resolution
of inflammation
INTRODUCTION
Inflammation is implicated in almost all of central nervous sys-
tem (CNS) diseases (Lo, 2010;Moskowitz et al., 2010;Iadecola
and Anrather, 2011). Neurodegeneration, infection, trauma, and
ischemia stimulate immune responses in the brain, although to
varying degrees. The process in neuronal injury involves various
intracellular mechanisms (abnormal metabolism and degenera-
tion of protein, dysfunction of organelles, etc.), which cause the
activation of microglia and the infiltration of circulating immune
cells (Lo, 2010). Inflammation may not be always main process in
the pathology of CNS diseases; nonetheless, the distinct charac-
teristics of ischemic stroke are large amount of necrotic neuronal
death and extreme infiltration of immune cells (Moskowitz et al.,
2010;Iadecola and Anrather, 2011).
Severe inflammation causes cerebral swelling, which is often
fatal in ischemic stroke patients. Broad necrotic lesion gener-
ates abundant inflammatory mediators and damage-associated
molecular patterns (DAMPs), which enhance the chemotaxis of
circulating immune cells and make them more efficient partici-
pants to promote inflammation (Moskowitz et al., 2010;Iadecola
and Anrather, 2011). Cerebral inflammation exaggerates vascular
dysfunction and induces further neuronal cell death (Dirnagl et al.,
1999). Thus, post-ischemic inflammation is an essential process in
the pathophysiology of ischemic stroke and is closely related to the
prognosis after stroke (Dirnagl et al., 1999;Lo, 2010;Moskowitz
et al., 2010;Iadecola and Anrather, 2011). In addition, inflamma-
tion is generally considered useful for the clearance of the large
amount of debris caused by brain cell necrotic death (Moskowitz
et al., 2010;Iadecola and Anrather, 2011). Inflammation, resolu-
tion of inflammation, and repair of neural damage are sequential
pivotal events after stroke. To clarify the detailed mechanisms of
each step of cerebral inflammation is indispensable to develop next
generation therapies for ischemic stroke. The molecular basis of
these steps is now being clarified by the recent accumulating evi-
dences. We summarize these findings and discuss the principles of
post-ischemic inflammation from beginning to end.
INFLAMMATORY DAMPs
Brain ischemia induces various large metabolic changes in brain
cells. Hypoxic stress, nutrients stress, and ER stress will cause cell
death and trigger post-ischemic inflammation. Although receptors
for pathogens such as Toll-like receptors (TLRs) are thought to be
involved in early step of inflammation, brain is a sterile organ.
Thus, endogenous molecules, i.e., DAMPs derived from injured
brain cells, must trigger the inflammatory response in immune
cells (Ta bl e 1 ). These DAMPs induce the activation of TLRs and
other pattern recognition receptors [receptor for advanced glyca-
tion end products (RAGE) and c-type lectin receptors], which
promote inflammatory mediator expression and tissue injury
(Figure 1;Tang et al., 2007;Yanai et al., 2009;Suzuki et al., 2013).
Recent scientific advances have suggested the existence of various
types of DAMPs in ischemic brain.
NUCLEIC ACIDS AND NUCLEOTIDES
Various intracellular components are released into the
extracellular space by necrotic brain cell death. Among these,
Frontiers in Cellular Neuroscience www.frontiersin.org October 2014 |Volume 8 |Article 319 |1
Shichita et al. Inflammatory mechanisms after ischemic stroke
Table 1 |List of inflammatory DAMPs.
DAMPs Receptor Reference
Signal 1 Nucleic acid Mitochondrial DNA TLR9 Zhang et al. (2010),Sun etal. (2013),Maeda and Fadeel (2014),Walko et al.
(2014),Wenceslau etal. (2014)
Self RNA, DNA TLR7,9 Hyakkoku etal. (2010),Kawai and Akira (2010),Brea et al. (2011),Stevens et al.
(2011),Leung et al. (2012)
Lipid Carboxyalkylpyrroles TLR2 West et al. (2010)
Oxidized phospholipids CD36 Cho et al. (2005),Gao et al. (2006),Abe et al. (2010),Haider etal. (2011),Miller
et al. (2011),Ho et al. (2012),Matt et al. (2013)
Protein HMGB1 TLR2,4, RAGE Qiu et al. (2008),Zhang et al. (2011)
Peroxiredoxin TLR2,4 Shichita et al. (2012),Kuang et al. (2014)
S100A8, A9 TLR4 Tsai et al. (2014)
Mrp8, 14 TLR4 Loser et al. (2010)
CIRP TLR2,4 Qiang et al. (2013)
Signal 2 Nucleotide ATP P2X, P2Y Martinon et al. (2002),Abulafia et al. (2009),Ceruti et al. (2009),Denes et al.
(2013),Fann et al. (2013),Yang etal. (2014),
Lipid Phospholipids ? Clemens et al. (1996),Bonventre etal. (1997),Muralikrishna Adibhatla and
Hatcher (2006),Shanta et al. (2012),Iyer etal. (2013),Zhong etal. (2013)
Protein ASC specks ? Baroja-Mazo et al. (2014),Franklin et al. (2014)
FIGURE 1 |Mechanisms of post-ischemic inflammation. DAMPs are
released into extracellular compartment and activate infiltrating immune
cells by two ways: Signal 1 (via the activation of pattern recognition
receptor) and Signal 2 (via the activation of inflammasome). Various
inflammatory cytokines promote neuronal injury, and induce further
inflammation mediated by T cells in subacute phase. After days and week
after stroke onset, the resolution of post-ischemic inflammation is brought
by the clearance of debris including DAMPs or inflammatory mediators,
and the production of anti-inflammatory molecules or neurotrophic factors.
In this recover phase, inflammatory immune cells turn into neuroprotective
cells.
nucleic acids and nucleotides are major DAMPs that have recently
received much attention. Mitochondrial DNA released by cellu-
lar injury can be detected as DAMPs by immune cells, because
mitochondria are considered to have a symbiotic origin that
carries numerous characteristics resembling bacteria. Mitochon-
drial DNA is a sensor molecule of innate immunity by activating
TLR9 and can be detected in cerebrospinal fluid after traumatic
brain injury (Zhang et al., 2010;Walko et al., 2014). Vascular per-
meability is also increased by circulating mitochondrial DNA
after injury (Sun et al., 2013;Wenceslau et al., 2014). Recently
accumulated data indicates that mitochondrial DAMPs could
be an important candidate for the trigger of post-ischemic
inflammation, even if there is not yet any direct evidence
(Maeda and Fadeel, 2014).
Self RNA and DNA (in complex with LL37 peptide) acti-
vate immune cells via TLR7 or TLR9 (Kawai and Akira, 2010).
TLR7 is associated with the deterioration in ischemic stroke
patients; in contrast, ischemic brain damage was not reduced
in TLR9-deficient mice (Hyakkoku et al., 2010;Brea et al., 2011).
Several reports demonstrate the implications of TLR7 and TLR9
in ischemic preconditioning. In these articles, the pretreatment
using a TLR7 or TLR9 agonist reveals significant neuroprotection
after cerebral ischemia by activating interferon regulatory factor
3/7- (IRF3/7)-induced type I interferon (IFN) signaling pathway
(Stevens et al., 2011;Leung et al., 2012). Although the interaction
between self nucleic acids and TLRs in the ischemic brain remains
controversial, ischemic preconditioning via the TLR7 or TLR9
signaling pathway may represent a therapeutic strategy.
Purines (ATP and UTP) released from injured brain cells and
their receptors, P2X and P2Y, function as alerting signals in CNS
(Ceruti et al., 2009). Importantly, ATP also activates inflamma-
somes, which are large multimolecular complexes that control the
activity of the proteolytic enzyme caspase-1 that cleaves pro-IL-1β
to an active 17 kDa form (Martinon et al., 2002). The activation of
Frontiers in Cellular Neuroscience www.frontiersin.org October 2014 |Volume 8 |Article 319 |2
Shichita et al. Inflammatory mechanisms after ischemic stroke
the NLRP1 or NALP3 inflammasome has been recently reported to
promote post-ischemic inflammation and neuronal death (Abu-
lafia et al., 2009;Fann et al., 2013;Yang et al., 2014). Because IL-1β
produced from both infiltrating immune cells and brain cells is
important (Denes et al., 2013), it should be clarified how the
inflammasome is activated in ischemic brain or hematopoietic
cells. Inhibition of the inflammasome activation pathway may be
a possible therapeutic strategy for ischemic stroke.
LIPIDS
Various types of lipids are also important regulators of innate
immunity. For example, oxidized low density lipoprotein (oxLDL)
is a popular inflammatory mediator, which activates TLRs
through binding with its receptor, CD36 (Stewart et al., 2010).
Although the function of oxLDL in ischemic brain remains
unclear, recent research has indicated that end products of
lipid oxidation may be implicated in cerebral post-ischemic
inflammation (Uchida, 2013). Carboxyalkylpyrroles, which are
generated in inflammatory tissue, activate TLR2 and promote
angiogenesis in ischemic organs (West et al., 2010). Oxidized
phospholipids are also generated during cerebral inflammation
and are considered to be DAMPs (Gao et al., 2006;Haider et al.,
2011;Ho et al., 2012). Oxidized phospholipids are CD36 lig-
ands that promote inflammation via TLR2 activation in ischemic
brain (Cho et al., 2005;Abe et al., 2010). The recognition and
endocytosis of oxidized lipids by pattern recognition receptors
could regulate post-ischemic inflammation (Miller et al., 2011;
Matt et al., 2013).
Phospholipids could also be inflammasome activators. Phos-
pholipid metabolism is drastically altered by cerebral ischemia
(Shanta et al., 2012). There are several reports showing the acti-
vation of phospholipase A2 (PLA2) in ischemic brain, which
results in hydrolysis of membrane phospholipids (Clemens
et al., 1996;Bonventre et al., 1997;Muralikrishna Adibhatla
and Hatcher, 2006). Phospholipid hydrolysis and mitochon-
drial dysfunction induced by cerebral ischemia generate reac-
tive oxygen species (ROS). Two recent studies have identi-
fied both ROS-dependent and ROS-independent pathways for
inflammasome activation. The former is demonstrated by a
charged phospholipid liposome that consecutively induces ROS-
dependent calcium influx and NLRP3 inflammasome activation
(Zhong et al., 2013). In the latter case, mitochondrial cardi-
olipin has been reported to directly bind to and activate the
NLRP3 inflammasome (Iyer et al., 2013). Thus, the metabolism
and modification of lipids during cerebral ischemia may be
closely associated with the post-ischemic inflammation start
signal.
PROTEINS
High mobility group box 1 (HMGB1) and peroxiredoxin (Prx)
family proteins are two major DAMPs in ischemic brain. There is
a difference in the functional phase of these two proteins (Shi-
chita et al., 2012). HMGB1, which is included in the nucleus
of brain cells, is released extracellularly at the hyperacute phase
(several hours after the stroke onset; Qiu et al., 2008). On the
other hand, Prx family proteins function at the acute and suba-
cute phases (12–72 h after the onset), especially in the penumbral
area (Shichita et al., 2012). This is because Prx family pro-
tein expression is induced by an intracellular increase in ROS,
which results from ischemic change. HMGB1 directly breaks
down the blood–brain barrier and increases vascular permeability
(Zhang et al., 2011). However, Prx directly induces the activa-
tion of infiltrating immune cells via TLR signaling. Ligustilide has
been reported as a therapeutic candidate that suppresses cerebral
post-ischemic inflammation by inhibiting the Prx/TLR4 signaling
pathway (Kuang et al., 2014).
S100A8, S100A9, Mrp8, Mrp14, and cold-inducible RNA bind-
ing protein (CIRP) have also been reported to be protein DAMPs,
although their relevance in post-ischemic inflammation has not
yet been clarified (Loser et al., 2010;Qiang et al., 2013;Tsai et al.,
2014). Inflammatory responses by these protein DAMPs occur
through the activation of TLR2, TLR4, and RAGE. TLR2 and TLR4
signaling pathways are essential for sterile inflammation, includ-
ing ischemic stroke (Chen et al., 2007). TLR2-blocking antibody
is neuroprotective against ischemic brain injury (Ziegler et al.,
2011). Similarly, resatorvid, which inhibits the TLR4 signaling
pathway, attenuates ischemic brain injury and also suppresses
Nox4-induced oxidative stress and neuronal apoptosis (Suzuki
et al., 2012). It is also possible that DAMP-mediated TLR activation
requires other adaptor molecules (Chun and Seong, 2010). CD14,
a TLR4 co-receptor, may be implicated in post-ischemic inflam-
mation (Reed-Geaghan et al., 2009). Heat shock protein gp96 is
another candidate molecule that functions as an adaptor for both
TLR2 and TLR4 (Yang et al., 2007).
It is not known whether protein DAMPs can activate inflamma-
somes. Recently, aggregated ASC (apoptosis-associated speck-like
protein containing a caspase recruitment domain) has been
reported to be released into the extracellular space after cell death
and it activates inflammasomes in the surrounding immune cells
(Baroja-Mazo et al., 2014;Franklin et al., 2014). Inflammasome
activation, which occurs through ASC polymerization, results
in caspase-1 activation and pyroptotic cell death. Extracellularly
released ASC is internalized by surrounding macrophages and
induces lysosomal damage and inflammasome activation. These
mechanisms of inflammasome activation remain to be elucidated
in ischemic brain injury.
OTHER INFLAMMATORY DAMPs
Basic research may neglect the influence of aging and life habits by
using healthy young rodents. These are important factors for the
generation of DAMPs. Aging and continuous high serum glucose
levels increase lipid peroxidation andAGEs in body systems (Basta
et al., 2004;Cai et al., 2014). AGEs are proteins that are modified
by sugar, through the Amadori and Maillard reaction. AGEs are
found in chronic lesions; for example, the amyloid deposits that
are surrounded by macrophages in patients with dialysis-related
amyloidosis (Miyata et al., 1993). Thus, AGEs usually take a long
time (more than a month) to generate; however, AGEs can be gen-
erated in a short period of time during inflammation (Weil, 2012).
Glyoxal and glyceraldehyde induce AGE formation within 1 week
(Takeuchi et al., 2001). In addition, the pivotal role of the RAGE
in post-ischemic inflammation has been demonstrated (Muham-
mad et al., 2008). AGEs can be a potential DAMP, especially in aged
human ischemic stroke patients.
Frontiers in Cellular Neuroscience www.frontiersin.org October 2014 |Volume 8 |Article 319 |3
Shichita et al. Inflammatory mechanisms after ischemic stroke
INFLAMMATION SUPPRESSION AND RESOLUTION
Activated immune cells and brain cells are the major play-
ers after various DAMPs trigger post-ischemic inflammation.
These cells produce inflammatory cytokines, chemokines, and
other cytotoxic mediators, and this leads to prolonged inflam-
mation and progressive brain edema during several days after
the stroke onset (Figure 1). However, post-ischemic inflam-
mation rarely lasts for a long period of time, and the most
intense inflammatory phase takes place within 7 days after stroke
onset (Dirnagl et al., 1999;Iadecola and Anrather, 2011). In
this phase, the number of infiltrating immune cells decreases
remarkably, and remaining immune cells in ischemic brain
produce anti-inflammatory or neurotrophic factors (Shichita
et al., 2009;Smirkin et al., 2010). For example, the detailed
mechanisms about the infiltration and the change to anti-
inflammatory phenotype of neutrophils have been recently clar-
ified (Cuartero et al., 2013;Gorina et al., 2014). The period
of cerebral post-ischemic inflammation always ends, and thus,
the mechanisms of its resolution must exist in ischemic
brain.
Three major points on the resolution of inflammation have
been discussed in a recent publication (Buckley et al., 2012).
These points are the production of anti-inflammatory media-
tors, the depletion of inflammatory mediators, and the induction
of anti-inflammatory immune cells. After post-ischemic inflam-
mation, infiltrating macrophages turn into anti-inflammatory
macrophages, which produce neurotropic factors and clear
necrotic debris. Inflammatory DAMPs will also be implicated
in the induction of anti-inflammatory macrophages, although
its mechanism still remains to be clarified. We introduce recent
advantages of the relationship between post-ischemic inflamma-
tion and its resolution.
ANTI-INFLAMMATORY MEDIATOR PRODUCTION
Many molecules have been reported to be neuroprotective factors.
However, most of these molecules failed to improve neurological
deficits in ischemic stroke patients, even if they are effective in
animal stroke models. It has been suggested that neuroprotection
alone is not sufficient to improve the prognosis of human ischemic
stroke. Anti-inflammatory mechanisms in the entire brain and
how these mechanisms are triggered needs to be determined.
Because most brain cells are dead in the ischemic region several
days after the stroke onset, infiltrating immune cells and reactive
glial cells could be major players in the tissue repair. In practice,
accelerating their effect is a potential next generation therapeutic
strategy, and direct in vivo reprogramming of reactive glial cells
into functional neurons after cerebral injury by retroviral trans-
duction of the NeuroD1 gene was recently reported (Guo et al.,
2014).
IL-10 and TGF-βare major anti-inflammatory molecules
in various organ injuries. Both are produced by infiltrating
immune cells and reactive glial cells after ischemic brain injury.
Viral overexpression of IL-10 in ischemic brain is neuroprotec-
tive (Ooboshi et al., 2006). One recent report demonstrated the
anti-inflammatory effect of TGF-βby inhibiting excessive neu-
roinflammation during the subacute phase of brain ischemia
(Cekanaviciute et al., 2014). Although the anti-inflammatory
effects of IL-10 and TGF-βhave been pivotal, it remains to be
clarified whether these effects last up to 1 week after the stroke
onset (Pál et al., 2012). If the mechanisms for stimulating TGF-β
and IL-10 expression can be controlled, this may become a strong
therapeutic method.
DEPLETION OF INFLAMMATORY MEDIATORS AND CELLS
Infiltrating immune cells and reactive glial cells produce various
inflammatory mediators. TNF-αand IL-1βdirectly induce neu-
ronal cell death. IL-23 and IL-1βactivate T cell-mediated innate
immunity and promote secondary ischemic damage during the
subacute phase of ischemic brain injury (Shichita et al., 2009;
Konoeda et al., 2010). The existence of these inflammatory medi-
ators, including DAMPs, prolongs post-ischemic inflammation
and will be a threat to neuronal survival and repair. How-
ever, inflammatory mediator degradation mechanisms remain
mostly unknown. Inflammatory molecules may be degraded by
some enzymes or consumed by receptor-mediated endocytosis.
It is expected that nucleotides and lipids are rapidly metabo-
lized in the ischemic brain, and transfer by the blood stream
or cerebrospinal fluid (CSF) will help to scavenge inflammatory
mediator. Further research should clarify the detailed mech-
anisms to scavenge inflammatory molecules produced in the
ischemic brain, and antibody therapy will be a pivotal thera-
peutic method targeting this potential mechanism. TNF-αand
IL-23 neutralizing antibody have been used clinically for rheuma-
toid arthritis and psoriasis patients, respectively. Natalizumab
is the neutralizing antibody for integrin-α4, which is neces-
sary for T cell infiltration into the inflammatory tissue, and has
already been used for multiple sclerosis (Yednock et al., 1992).
T cell depletion from ischemic brain has received attention as
a potential next generation therapy for ischemic stroke (Meisel
and Meisel, 2011;Wei et al., 2011). Thus, antibody therapies
may be used to help treat ischemic stroke patients in the near
future.
Activation of inflammasomes in immune cells induces the pro-
duction of IL-1βin its mature form, and finally results in the rapid
cell death of the same cells, which is called pyroptosis. Pyroptosis
may be a possible mechanism for the clearance of inflammatory
immune cells. This is supported by the fact that dying cells detected
using the TdT-mediated dUTP nick end labeling (TUNEL) stain-
ing method include macrophages and glial cells in the ischemic
brain (Mabuchi et al., 2000).
INDUCTION OF IMMUNE CELL REPAIR
The repair process for damaged brain tissues and regeneration
of neural cells takes place during resolution of inflammation. It
is difficult to separate this process from the anti-inflammatory
mechanism, because they may overlap each other. We will fur-
ther discuss neuroprotective factors and repairing the damage to
immune cells.
NEUROPROTECTIVE FACTORS
Various growth factors are also produced by immune cells and
glial cells (Gudi et al., 2011). Among these, IGF-1 and FGF-2
are produced by infiltrating macrophages and microglia dur-
ing the recovery phase of ischemic brain injury (which occurs
Frontiers in Cellular Neuroscience www.frontiersin.org October 2014 |Volume 8 |Article 319 |4
Shichita et al. Inflammatory mechanisms after ischemic stroke
1 week after the stroke onset). IGF-1 and FGF-2 improve the
neurological outcome by saving neuron and glial cells from
cell death (Ness et al., 2004;Ikeda et al., 2005;Zhu et al., 2008;
Hill et al., 2012;Lalancette-Hébert et al., 2012). IGF-1 also
enhances repair after ischemic stroke by promoting neural regen-
eration, remyelination, and synaptogenesis (Lecker et al., 2007;
Zhu et al., 2008,2009;Kooijman et al., 2009). Further inves-
tigation should clarify the mechanisms of IGF-1 and FGF-2
induction in the ischemic brain. Recently, transfer of mesenchy-
mal stem cells (MSCs) has been explored as a next generation
therapy for ischemic stroke (Kalladka and Muir, 2014). MSCs
produce various growth factors and promote neuronal survival
and neurogenesis (Calió et al., 2014). By improving the transfer
method, cell therapy may become a pivotal therapeutic strategy
(Guo et al., 2013).
The neuroprotective effect of prostaglandin E2 (PGE2) and
its receptor signaling pathway has received recent attention.
PGE2 has an effect via four distinct G protein-coupled EP
receptors (E-prostanoid: EP1, EP2, EP3, and EP4). The activa-
tion of EP2 signaling has a neuroprotective effect in ischemic
brain injury, which was shown in the significant increase in
infarct volume in mice lacking the EP2 receptor (McCullough
et al., 2004). Similarly, signaling via the EP4 receptor, which is
expressed in both neurons and ischemic endothelial cells, has
neuroprotective effects against ischemic brain injury (Liang et al.,
2011). The administration of an EP4 agonist reduces infarct vol-
ume and neurological deficits. In a neonatal hypoxic-ischemic
encephalopathy model, the inhibition of EP1 receptor signal-
ing or the activation of EP2, EP3, and EP4 receptor signaling
reveals attenuation of the ischemic injury (Taniguchi et al., 2011).
PGE2 and EP receptor signaling pathways have various func-
tions, which are dependent on distinct pathology of cerebral
diseases (Furuyashiki and Narumiya, 2011). Targeting specific
EP receptors in ischemic brain may become a novel therapeutic
method.
Similar to PGE2, some lipids have been reported to have anti-
inflammatory effects and promote neuroregeneration (Serhan,
2014). Cerebral ischemia increases PLA2 activity, which results in
the hydrolysis of phospholipids in the cellular membrane (Shanta
et al., 2012). Although the PLA2 effect itself is cytotoxic because
it disrupts the cellular membrane, PLA2 also generates docosa-
hexaenoic acid (DHA) derivatives and lysophospholipids through
phospholipid hydrolysis (Bonventre et al., 1997). Resolvin and
Neuroprotectin have been investigated for their anti-inflammatory
function in ischemic stroke (Marcheselli et al., 2003;Bazan, 2009).
Lysophospholipids also increase in ischemic brain and promote
neurite outgrowth (Ikeno et al., 2005;Spohr et al., 2011;Shanta
et al., 2012). Regulating the effect of these lipids is expected for the
resolution of post-ischemic inflammation.
NEUROPROTECTIVE CELLS
Inflammatory DAMPs activate glial cells and infiltrating immune
cells to promote post-ischemic inflammation. Paradoxically, this
mechanism results in the infiltrating macrophage cell death and
also induces anti-inflammatory and tissue-repairing immune cells.
Immune cell activation also induces anti-inflammatory cells.
These cells have been called M2 macrophages, in contrast to the
inflammatory M1 macrophages. Many researches have described
the M2 macrophage markers; these markers include: arginase-
1 (Arg1), chitinase3l3 (Ym), and Relmα(Fizz1). These markers
are intracellular enzymes that are implicated in collagen synthesis
and cell division; therefore, M2 enzymes are considered to pro-
mote tissue repair. Arg1 is the only marker that was reported
to function as a neuroprotective enzyme (Estévez et al., 2006).
However, these M2 markers may not be a good indicator for
recovery after ischemic stroke. M2 markers are rapidly expressed
in macrophages by TLR activation or other pattern recognition
receptors, which also induce inflammatory cytokine expression
(Hu et al., 2012). M2 markers appear in ischemic brain mostly
during the same phase as the inflammatory mediators, the M1
markers, are expressed. In addition, the transfer of M2 marker
positive-macrophages has not been reported to be sufficiently
neuroprotective (Desestret et al., 2013).
During post-ischemic inflammation, some populations of
macrophages and microglia become neuroprotective (Lalancette-
Hébert et al., 2007). Galectin-1 has been suggested to be
an inducer of anti-inflammatory macrophage/microglial cells
(Starossom et al., 2012;Quintá et al., 2014). Galectin-1 is pro-
duced by astrocytes and has a neuroprotective effect against
ischemic brain damage (Qu et al., 2011). Thus, the resolu-
tion of post-ischemic inflammation can be enhanced by the
induction of a specific macrophage/microglial cell population.
However, it is not clear whether the M2 markers truly reflect
the neuroprotective function of macrophages and microglial
cells. Suppressing inflammation alone is not enough to pro-
tect the brain from ischemic injury. IGF-1 and FGF-2 pro-
duction seems to be a good index of repairing function
(Lalancette-Hébert et al., 2012).
Further study is required to clarify whether sufficient clear-
ance of inflammatory mediators (including DAMPs) begins
neuronal regeneration after ischemic stroke. A recent study
has suggested that there is a relationship between TLR activa-
tion and neuronal repair (Bohacek et al., 2012). It is possible
that DAMPs triggers the secondary signals, which lead to res-
olution of post-ischemic inflammation, even if the primary
signals via pattern recognition receptors promote ischemic dam-
age. What is this mechanism? The role of immune cells, other
than macrophages and microglia in part of the repair process,
is not fully understood. This understanding may be critical
for the establishment of next generation therapies for ischemic
stroke.
CONCLUSION
Immunity and various physiological mechanisms are implicated in
the triggering, persistence, and resolution of post-ischemic inflam-
mation. Recent accumulating evidences clarify the complexity of
these mechanisms to understand the entire mechanisms. They will
show promising potential targets to develop therapies for ischemic
stroke.
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Conflict of Interest Statement: The authors declare that the research was conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 28 July 2014; accepted: 23 September 2014; published online: 14 October
2014.
Citation: Shichita T, Ito M and Yoshimura A (2014) Post-ischemic inflamma-
tion regulates neural damage and protection. Front. Cell. Neurosci. 8:319. doi:
10.3389/fncel.2014.00319
This article was submitted to the journal Frontiers in Cellular Neuroscience.
Copyright © 2014 Shichita, Ito and Yoshimura. This is an open-access article distributed
under the terms of the Creative Commons Attribution License (CC BY). The use, dis-
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