Chapter 14
Glial Cells in Brain Defense Mechanisms
Mami Noda
Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University,
Higashi-ku, Fukuoka, Japan
1 INTRODUCTION: GLIAL CELLS IN
THE BRAIN
In the brain, glial cells are considered to be the patho-
logic response element. Glia, represented by astrocytes,
oligodendrocytes and microglial cells, provide for numer-
ous vital functions, though they had been long ignored and
regarded as mere support staff for the all-important neurons.
The emerging realization of the importance of glia has given
new life to an idea that has long lurked at the margins of neu-
roscience: that glia may have key roles in central nervous
system disorders ranging from neuropathic pain and epilepsy
to neurodegenerative diseases such as Alzheimer’s disease
and may even contribute to schizophrenia, depression and
other psychiatric disorders. There are also hints that glia may
be promising therapeutic targets [1].
Glial cells shape the micro-architecture of the brain matter,
and are involved in information transfer by virtue of numer-
ous plasmalemmal receptors and channels. Recent advances
in gliology emphasized the role of glia in the progression and
handling of insults to the nervous system. Brain pathology is,
to a very great extent, a pathology of glia, which determines
the degree of neuronal death, the outcome and the scale of
neurological deficit. Glial cells are central in providing for
brain homeostasis. In addition, glia are intrinsically endowed
with two opposing features: they protect nervous tissue, but
can also rapidly assume the guise of a natural killer, trying
to eliminate and seal off a damaged area so as to salvage the
whole at the expense of the part.
Glial cells can respond to infections, lesions or trauma
through the production of cytokines and chemokines.
Although specific interactions between resident glia and lym-
phocytes that infiltrate the infected brain remain to be defined,
the presence of T cell chemotactic signals in microglial cell
supernatants following infection or lesion has led to the con-
cept that chemokines initiate a cascade of neuroimmune
The Brain and Host Defense
Copyright © 2010
2009 by Elsevier B. V. All rights of reproduction in any form reserved.
responses that result in defense of the brain. While chemok-
ines may play a defensive role by attracting T cells into the
brain, aberrant accumulation of lymphocytes may also induce
brain damage. Host defense mechanisms must balance control
of herpes virus spread, with associated undesirable immun-
opathologic effects. A growing body of evidence suggests that
through complex networks of chemokines and cytokines pro-
duced in response to herpes virus infection, glial cells orches-
trate a cascade of events that result in either successful defense
of, or damage to, the brain.
2 MICROGLIA
Among glial cells, microglia are the macrophages of the cen-
tral nervous system. Microglia have complex roles. They can
either protect or damage neurons, depending on where and
how they are activated [2]. Recent findings indicate that neu-
rons are not merely passive targets of microglia, but rather
that they control microglial activity. The variety of different
signals that neurons use to control microglia can be divided
into two categories: “off” signals constitutively keep micro-
glia in their resting state and antagonize pro-inflamma-
tory activity; while “on” signals are inducible, and include
purines, chemokines, glutamate and various neuropeptides.
They drive microglial activation under pathological condi-
tions towards a beneficial or detrimental phenotype. Various
neuronal signaling molecules thus actively control microglia
function, thereby contributing to the inflammatory milieu of
the central nervous system. Thus, neurons should be envis-
aged as key immune modulators in the brain [3].
Nevertheless, following any type of brain injury such
as lesion, stroke, or tumor/cancer invasion, microglia are
rapidly activated [4, 5] and recruited to the site of injury.
Microglia constitute the main immune effector cell popu-
lation of the central nervous system (CNS) and control
161
162
immune cell recruitment. Under pathological conditions,
activated microglia can phagocytose dead cells and clear
cellular debris at the site of injury [6–8]. There are several
candidate molecules which serve as signals for pathologic
events to microglia. As has recently been shown [9], micro-
glial processes rapidly respond to ATP in vivo, and ATP has
been reported to be a chemoattractant for microglial cells
[10]. A variety of other signals stimulate microglial motility,
such as cannabinoids [11], morphine [12], or the chemokine
CCL21 [13]. Neuropeptides, including bradykinin, com-
prise another family of candidates [14]. Indeed, bradykinin
attracts microglia both in vitro and in vivo [15]. Therefore,
some neuropeptides produced at the site of injury attract
microglia together with ATP (Figure 14.1).
2.1 Signal Cascade of Microglial Migration
It was reported that ATP-induced microglial migration was
inhibited by pertussis toxin (PTX), suggesting that activation
of Gi/o proteins induced by P2Y receptors is part of the intra-
cellular signaling cascade controlling microglial migration
[10]. On the other hand, the importance of Ca2⫹-activated
K⫹ channels for migration of microglia was inferred from
studies stimulating microglia with lysophosphatidic acid
[16]. Some neuropeptides increase microglial migration. As
a typical example, the bradykinin-induced increase in micro-
glial migration and its underlying signaling cascade indi-
cated that it involves its inducible receptors (B1 receptors)
and pertussis toxin-independent G protein, most likely Gq/11
protein, which activates phospholipase C (PLC) with conse-
quent activation of protein kinase C (PKC) and diacylglyc-
erol (DAG). PKC may phosphorylate and activate Na⫹/Ca2⫹
exchanger (NCX) in reverse-mode, inducing Ca2⫹ influx
from outside the cell membrane [15]. Activation of DAG and
consequent formation of inositol 1,4,5-trisphosphate (IP3) is
another possible mechanism for increasing intracellular Ca2⫹
concentration by mobilization of intracellular Ca2⫹ stores.
ATP, chemokines,
neuropeptides
Microglia
Neurons
Astrocytes
FIGURE 14.1 Proposed actions of ATP and various neuropeptides under pathologic conditions.
Left: in response to a pathologic event, adenosine trisphosphate (ATP) and neuropeptides such as galanin and bradykinin are released. Right: microglial cells are
attracted to the lesion site or inflammatory site. Neuropeptides have negative feedback on the release of inflammatory cytokines such as TNFα and IL-1β from micro-
glia, and this is a potential neuroprotective mechanism. Microglial NO release is less evident, since it could both affect neurons and the vascular system (right).
Modified from Noda et al. [59].
SECTION | IV How the Brain Defends Itself
Increase in intracellular Ca2⫹ activates Ca2⫹-dependent
⫹
K (KCa) channels. The precise mechanism by which activa-
tion of KCa channels induces microglial migration is not yet
known, but it is speculated that hyperpolarization induced by
KCa currents increases the driving force (the electrochemical
gradient) for Ca2⫹ influx, and thus enhances the intracellular
Ca2⫹ signal required to stimulate cell migration [15].
Apart from PLC cascade followed by activation of
Gq/11, activation of phosphoinositide-3 kinase (PI3K) may
also be involved in the activation of NCX or ATP-induced
microglial migration (Figure 14.2).
2.2 The Role of Attracted Microglia
The physiological and pathophysiological roles of micro-
glia attracted to a lesion site or inflammatory area are
contradictory. One of the peptides, bradykinin, has been
reported to be a mediator of brain damage in acute insults.
It is widely regarded as causing pain and inflammation.
However, bradykinin does not induce the release of any
inflammatory cytokines, such as tumor necrosis factor-
alpha (TNFα) or interleukin-1β (IL-1β), from microglia.
Rather, it attenuates lipopolysaccharide (LPS)-induced
release of TNFα and IL1-β from microglial cells, thus
acting as an anti-inflammatory mediator in the brain. A
signaling schema explaining how neuropeptides such as
bradykinin might attenuate LPS-induced TNFα release is
shown in Figure 14.3. The principal effect of neuropeptides
is to enhance both prostaglandin synthesis and prostanoid
receptor expression, thereby enhancing microglial cAMP
production, which in turn inhibits LPS-induced TGFα
release – an effect that may be amplified by upregulation
of neuropeptide receptors. The same mechanism might
also apply to the inhibition of IL-1β release. This provides
an amplified negative feedback mechanism for TNFα and
IL-1β production in microglia, thereby accounting for the
neuroprotective action of neuropeptides.
PGE2
TNFα
PGE2
IL-1β
NO
Blood vessel
Chapter | 14 Glial Cells in Brain Defense Mechanisms 163

3 CANDIDATE NEURON–MICROGLIA 3.2 Purines

SIGNALING FACTORS
Damaged neurons are abutted by activated microglia in vivo
within hours after injury, which suggests that neurons emit
signals that attract these cells [17]. Endangered neurons
release chemokines, purines [18, 19] and various neuro-
peptides [20]. In addition, excessive glutamate, matrix
metalloproteinases (MMPs) and DAP12 are also important
for neuron–microglia signaling.
3.1 Chemokines
Chemokines such as CX3CL1, CCL21 and CXCL10 [21–24]
attract microglia to damaged neurons [23]. This notion is
corroborated by in vivo data derived from chemokine-defi-
cient or chemokine-receptor-deficient animals, in which
impaired microglial migration [25, 26] and delayed or
diminished microglial activation were found in response to
neuronal death [26]. Moreover, CX3CL1-CX3CR1 might
signal microglia in the spinal cord after peripheral nerve
injury in mouse models of neuropathic pain [27].
Another neuron–microglia signaling system which causes
neuropathic pain involves purines [18], including ATP and
UTP [19, 28]. They are released or leaked from damaged or
overly active neurons. Microglia express purin receptors –
mainly P2⌾4 and P2⌾7, but also P2Y2, P2Y6 and P2Y12
[29]. From in vitro studies, purines trigger various responses
in cultured microglia [10, 29–31]. Recent in vivo experi-
ments have convincingly confirmed a role for purines as
potential neuronal signals [9, 32]. Other microglial purine
receptors are upregulated in vivo after neuronal damage, as
has been demonstrated for P2Y6. This receptor is not involved
in microglial morphological changes, but triggers microglial
phagocytosis [19]. Moreover, an induction of microglial P2⌾4
expression was demonstrated in vivo in the spinal cord after
peripheral nerve injury. Accordingly, inhibition of ATP sign-
aling or P2⌾4 function in mouse microglia prevented tactile
allodynia, a hallmark of neuropathic pain that can also occur
in humans after peripheral nerve injury [18, 27]. Recently,
direct evidence that P2⌾4R stimulation leads to the release of
BDNF from activated microglia was shown, as well as possi-
ble phosphorylation of the NR1 subunit of NMDA receptors in

Tissue injury
Neuropeptides inflammation
and its metabolites
K+ K+
Ca2+
ATP

Receptors NCX P2Y

Gi/o
Gq/11 P Ca2+
3Na+
Ras
Ca2+-dependent
Raf K+ channel
Phosphorylation? MAPK
Phospholipase C
Hyperpolarization
MAPK and Ca2+ influx?

MEK PKC
IP3 Ca2+i
ERK Motility
PI3K
chemotaxis

FIGURE 14.2 Production of neuropeptides after tissue injury or inflammation and their signaling cascade in microglia.
Some neuropeptides and ATP are produced at sites of tissue injury or inflammation. Some neuropeptides are also produced at the site of injury. Many of the neu-
ropeptides activate their receptors which often couple to Gq/11 protein, resulting in the activation of phospholipase C (PLC) and protein kinase C (PKC). PKC can
phosphorylate Na⫹/Ca2⫹ exchanger (NCX) and increase NCX activity. Either inositol 1,4,5-trisphosphate (IP3)-induced intracellular Ca2⫹ mobilization or PKC-
induced activation of reverse mode of NCX increases intracellular Ca2⫹. Increase in intercellular Ca2⫹ can activate Ca2⫹-dependent K⫹ channels. Resulting hyper-
polarization may induce microglial motility and chemotaxis. On the other hand, adenosine trisphosphate (ATP) induces microglial migration by activation of ATP
receptors (mostly P2Y12 receptor), which couple to pertussis toxin-sensitive Gi/o protein. Activation of some neuropeptide receptors and ATP receptors (mostly
P2Y12 receptor) also couples to mitogen-activated protein kinase (MAPK) signaling, which involves activation of Ras and consecutive stimulation of phospho-
inositide 3-kinase (PI3K). PI3K was involved in a part of microglial motility.
Modified from Ifuko et al. [15].
164 SECTION | IV How the Brain Defends Itself

Negative feedback

Neuropeptides

+
Receptors
Gi/o ?
Gq/11
Trauma
IL-1β ↑ Migration
inflammation
LPS TNF-α ↑
[Ca2+] ↑ I(KCa)

+ Gs
EP2-R
PGE2 ↑ cAMP ↑
EP4-R

+
NF-κB ?

Upregulation
FIGURE 14.3 A proposed schema for the inhibitory effects of neuropeptides on lipopolysaccharide (LPS)-induced TNFα and IL-1β release from
microglia.
Neuropeptides activate their receptors, which activate Gq/11, that mobilizes intracellular Ca2⫹, inducing a Ca2⫹-dependent K⫹ current IK(Ca) and subsequent micro-
glial migration, whose precise signaling was shown in Figure 14.2. Some neuropeptides, such as bradykinin, also release PGE2. This induces a negative-feedback
inhibition of LPS-induced TNFα and IL-1β release, mediated by cyclic AMP, and a positive-feedback increase in receptor expression. LPS-induced TNFα release
also upregulates EP2/EP4 receptors and neuropeptide receptors, probably through the activation of NFκB. LPS itself may exert a negative-feedback inhibition of
its own on TNFα release via PGE2 and prostanoid receptors and cAMP.
Modified from Noda et al. [60].

dorsal horn neurons of the spinal cord. Consistent with these
findings, P2⌾4-deficient mice lack mechanical hyperalge-
sia induced by peripheral nerve injury and display impaired
BDNF signaling in the spinal cord [33].
3.3 Glutamate
Excessive neuronal glutamate release is associated with neuro-
degenerative processes. Glutamate directly leads to neuronal
death, but also serves as an activation signal for microglia
[34, 35]. In culture, microglia express a variety of glutamate
receptors (GluRs), such as AMPA-type GluR1-GluR4, kainate
receptors [36, 37], and members of all three groups of metab-
otropic glutamate receptors (mGluRs) [38–40]. Activation of
various glutamate receptors triggers release of TNFα [36, 37],
which in concert with microglial-derived Fas ligand leads to
neurotoxicity [41]. In another in vitro study, it was shown that
activation of microglial mGluR2 protects striatal dopaminergic
neurons against MPP⫹ (N-methyl-4-phenylpyridinium cat-
ion)-induced toxicity, which was attributed to microglial pro-
duction of brain-derived neurotrophic factor (BDNF) [42].
Activation of group III mGlu receptors in vitro induced mild,
but not neurotoxic, activation of microglia, and reduced LPS
and chromogranin A-induced microglial neurotoxicity, which
suggests that group III mGlu receptors suppress the produc-
tion of microglia-derived neurotoxins [39].
3.4 Matrix metalloproteinases (MMPs)
MMPs are proteolytic enzymes that degrade extracellular
macromolecules and are involved in tissue remodeling,
cell migration, wound healing, angiogenesis and various
neuropathological conditions [43]. Studies on several CNS
diseases, like ischemia, Alzheimer’s disease and multiple
sclerosis, suggest that MMP-3 might play an important
role in neurodegeneration [44–46]. Compelling evidence
for neuronal release of the active form of MMP-3 is pro-
vided by a study that reported release of MMP-3 from
apoptotic neuronal cell lines and apoptotic mesencephalic
neuronal cultures [47, 48]. It was shown that the catalytic
domain of recombinant MMP-3 (cMMP-3) mediates the
release of TNFα, IL-6, IL-1β and IL-1 receptor antagonist
into the supernatant of microglia cultures. Thus, the release
of MMP-3 can be considered instrumental and a direct
neuroglial apoptosis signal in neurodegeneration. In addi-
tion, MMP2 and MMP9 provide the latest example, with
converging roles in chronic pain after peripheral nerve
injury. Two matrix metalloproteases, MMP2 and MMP9,
upregulated in neurons, astrocytes and satellite cells, medi-
ate changes involved in pain hypersensitivity after nerve
injury, acting through IL-1β. The MMPs seem to have
no role in acute pain, but blocking their activity dampens
chronic pain in a mouse model of peripheral neuropathic
pain [49, 50].
Chapter | 14 Glial Cells in Brain Defense Mechanisms
3.5 TREM2–DAP12 Signaling
TREM2 (triggering receptor expressed on myeloid cells 2)
is a recently identified innate immune receptor associated
with the signaling molecule DAP12. TREM2 and DAP12
are expressed on microglia, immature dendritic cells and
osteoclasts [51]. Disturbed microglial clearance function and
osteoclast bone resorption impairment appear to be responsi-
ble for the brain and bone symptoms, respectively, in Nasu-
Hakola disease or PLOSL, a recessively inherited disease
with early onset adult dementia and bone cyst formation [52].
Stimulation of TREM2 induced phosphorylation of DAP12
and increased phagocytotic activity of microglia in culture.
Knockdown of TREM2 in microglia inhibited phagocytosis
of apoptotic neurons and increased gene transcription of the
pro-inflammatory mediators TNFα and NO synthase-2 [53].
The unexpected finding that TREM2–DAP12 signaling had
anti-inflammatory effects was also observed in macrophages
[54]. Thus, TREM2 deficiency possibly results in impaired
clearance of apoptotic neurons and causes pro-inflammatory
cytokine production, which indicates that TREM2–DAP12
signaling is responsible for CNS immune homeostasis by
shutting down microglial inflammatory activity.
3.6 Superoxide Dismutase (SOD)
Amyotrophic lateral sclerosis (ALS) is a disease character-
ized by the selective degeneration of motor neurons. The
only known genetic cause of the disease, which accounts for
about 2 percent of cases, is a mutation in the gene encod-
ing superoxide dismutase 1 (SOD1) protein. Therefore, the
effect of mutant SOD1 has been intensely studied, especially
in glial cells, ever since it was suggested that astrocytes [55]
and microglial cells [56–58] serve as potential contributors
to motor neuron injury in ALS. The expression of mutant
SOD1 in microglia accelerates the death of motor neurons in
mouse models of SOD1-linked ALS. The cause may be toxin
production or the transfer of toxins to nearby motor neurons
or astrocytes by mutant microglia, or the mutant protein
may damage the microglia and prevent them from produc-
ing protective factors. Other possibilities exist, including the
production of diffusible toxins (such as ions or cytokines) by
damaged microglia. There are interesting findings that onset
and progression represent distinct disease phases defined by
mutant action within different cell types to generate non-cell-
autonomous killing of motor neurons [57, 58].
3.7 Neuropeptides
Many neuropeptides and hormonal peptides have been iden-
tified on the basis of bioassays, but their effects on glial func-
tion are poorly understood. Functional analyses of bradykinin
on microglia and its neuroprotective effects [15, 59, 60], as
described above, may trigger interest in newer concepts of
165
neuron–glia interaction. Although the contribution of neu-
ropeptides to microglial signaling has not been fully investi-
gated as yet, it might be advanced substantially by a better
understanding of the role of microglia in the physiological
mechanisms underlying sleep, diet and emotion. Dysfunction
of microglial signaling may contribute to neurological or psy-
chological disorders, including depression and schizophrenia.
4 CONCLUSIONS
There is increasing evidence that both neurons and glial cells
play crucial roles in the control of cell function in the brain.
Among glial cells, microglia are the macrophages of the cen-
tral nervous system. They are the primary immune effector
cells in the brain and highly dynamic surveillants of brain
parenchyma [61]. Many signals derived from neurons seem to
be important for maintaining tissue homeostasis and restrict-
ing microglial activity under inflammatory conditions, most
likely to prevent damage in unaffected parts of the brain. It
is unclear to what extent these signals might also contribute
to the immune control of the healthy, non-inflamed CNS. On
the other hand, different signals are expressed in damaged or
impaired neurons that activate either supportive or neurotoxic
microglial functions. Identification of the neuron-derived sig-
naling pathways might contribute to the development of new
therapies for neurodegenerative diseases. Traditionally, neu-
rons have been implicated as the sole targets of microglial
cytotoxicity – innocent victims of overly activated immune
cells. It is now clear that neurons actively control microglial
function [3], thereby making a contribution to the inflamma-
tory milieu of the CNS. Thus, neuron–glial interaction can be
envisaged as key to immune modulation in the brain.
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