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Introduction
Amoeboid microglial cells (AMC), the nascent form of ramified microglia that persist in the adult brain, are present
ubiquitously in the brain during fetal and early postnatal development. They are present transiently until 10_14 d of age
(Figure 1A) when all of them transform into the adult, ramified microglial cells (Figure 1B). There is recent evidence that the
ramification of AMC may be regulated by cytoskeletal elements as transfection of the cells with a cytoskeleton-related gene,
in particular, juxtanodin has resulted in the branching of the cells assuming a ramified external morphology (Figure 2). AMC
exist singly or in clusters in the subventricular white matter. Other areas in which AMC are preponderant include the cavum
septum pellucidum and subependymal cysts closely associated with the third and fourth ventricles and the cerebral aqueduct.
In the brain tissue, the cells are widely distributed; some of them may be spatially associated with neurons, blood vessels, or
dispersed freely. The close association of AMC to blood vessels has been reported in many areas of the
brain[1_3].
The origin and mode of the formation of AMC has been a contentious issue for decades, and many theories had been
proposed since the first description of a cellular "third
element" other than neurons and
neuroglia[4] and identification of microglia by del
Rio-Hortega[4,5]. Three hypotheses have
been put forward in relation to the origin of microglia: (i)
mesodermal[6,7]; (ii)
neuroectodermal[8_10]; and (iii)
monocytic[11_13] . Investigations carried out in our laboratory over the
past 3 decades tend to support the monocytic origin of AMC,
although the possibility that these cells may be derived by
direct invasion of fetal macrophages cannot be
excluded[14]. We have shown that circulating monocytes invade the brain
during embryonic and early postnatal life and then
transform into AMC; hence, they are monocyte-derived brain
macrophages like other tissue macrophages.
Nature of AMC
AMC are multifunctional immune cells in the developing
central nervous system (CNS) that play an important role in
the defense of neural parenchyma. Early studies have shown
AMC to be active macrophages in the developing
brain[13,15], removing cellular debris during normal development as well
as in pathological conditions. Besides their scavenging
function, AMC may also exert a cytotoxic effect through the
secretion of toxic factors, such as nitric
oxide[16]. Recent studies in our laboratory have greatly amplified the
functional roles of these cells during development, in addition to
their primary role in phagocytosis.
AMC function as phagocytes The phagocytic nature of
AMC has been shown by various methods and observations,
including the localization of hydrolytic enzymes,
ultrastructural features shared by tissue macrophages, uptake of
exogenous substances, and the activation of surface
receptors and antigens related to phagocytosis.
Hydrolytic enzymes Our early cytochemical studies
have shown the presence of hydrolytic enzymes, including
acid phosphatase, aryl phosphatase, non-specific esterase
and 5'-nucleotidase in the lysosomes in
AMC[12,17,18]. The high contents of these hydrolytic enzymes in AMC
suggested that these cells were active macrophages. This
observation is supported by recent studies which have reported
the localization of hydrolytic enzymes, such as acid
phosphatase in macrophages, in the pineal
gland[19]. A study investigating the ability of peritoneal, alveolar, and splenic
macrophages and Kupffer cells to kill
pathogens[20] reported that acid phosphatase activity was significantly increased
in macrophages which ingested the pathogens and killed
them. In vitro studies have shown that AMC were
phagocytic and possessed non-specific esterase
activity[21]. With time, these cells transform into ramified microglia-like cells
and lose their phagocytic property as well as non-specific
esterase content[21].
Ultrastructural observations Ultrastructural studies
carried out in our laboratory in the normal postnatal brain
and in the brains of rats subjected to hypoxia or
Escheria coli(E coli) treatment have supported the phagocytic
property of AMC. The macrophagic nature of AMC was
evidenced by their engagement in the phagocytosis of
degenerating axons and cells in the normal developing
brain[22]. Under the electron microscope, some AMC in the corpus
callosum of postnatal rats were observed to extrude
portions of their cytoplasm which were phagocytosed by
neighbouring AMC[22].
In the fetal and postnatal rat brains, AMC were found to
phagocytose dead cells in the brain after transient maternal
hypoxia[23]. Neonatal rats exposed to hypoxia also showed
AMC in the corpus callosum engaged in the phagocytosis
of apoptotic cells[24] and degenerating
axons[16]. Further evidence of the phagocytic nature of AMC comes from their
involvement in the removal of E coli introduced directly into
the neonatal brain. Many of the injected E.
coli were sequestered by AMC in less than 3
h[25]. It was concluded from these observations that AMC form a protective barrier which
is deemed to be necessary in the early developmental period
when the blood-brain barrier (BBB) is deficient.
Tracer studies It is well established that the BBB in the
developing brain is immature. Administration of tracers, such
as rhodamine isothiocyanate and horseradish peroxidase
(HRP), intraperitoneally or intravenously, resulted in the
labeling of AMC in the corpus callosum and other
regions[26,27]. This suggested that substances in circulation leaked through
the immature BBB and were phagocytosed by AMC. Another tracer, biotinylated dextran, when injected in various
areas of the brain far removed from the corpus callosum, also
resulted in the labeling of AMC[28]. It was concluded that
AMC become labeled by ingesting the tracer which diffused
slowly through the extracellular spaces from the injection
site. Injection of HRP in the lumbosacral region of the spinal
cord also resulted in the labeling of AMC in the corpus
callosum[29]. The results suggested an ascending diffusion of
the injected HRP in the spinal cord via wide interstitial spaces
to reach the cerebrum where it was engulfed by the AMC.
ED1 antigens Further support to the macrophagic
nature of AMC was lent by the expression of ED1 antigens on
these cells. ED1 antigens are expressed by cells of
monocyte/macrophage lineage[30]. These antigens were expressed
by AMC in the fetal[31] and postnatal
period[32], but not in adult rats.
Complement type 3 receptors Complement type 3
receptors (CR3) were detected on the cell membranes of AMC
by using the antibody OX-42. It was proposed that these
receptors are related to the active role of AMC in
endocytosis[33]. This was supported by reports that CR3 receptors on
monocytes and their derivative macrophages mediate
endocytosis[34_37].
Lectin histochemistry Microglial cells engulfing
pyknotic and fragmented nuclei of cells undergoing programmed
cell death have also been visualized by use of lectin
histochemical staining in conjunction with cresyl violet
counterstaining[38].
Antigen presentation Although the CNS, under normal
conditions, has been considered an immunologically
privileged site for a long time, our studies showed for the first
time that major histocompatibility class (MHC) I antigens
were expressed by AMC[39]. MHC antigens are surface
molecules required for the participation of macrophages in the
activation of T lymphocytes by presenting certain antigens
to them. MHC I antigens serve as restriction elements for
cytotoxic/suppressor lymphocytes[40,41]. The expression of
these antigens on AMC was related to their phagocytic
activity[39]. The presence of MHC I antigens on AMC also
suggests that these cells are ready to interact with
infiltrating lymphocytes as the BBB is immature in the developing
brain and the danger of a potential immune threat in early
development may be present.
MHC II antigens, required for interaction with
helper/inducer T lymphocytes, on the other hand, are not expressed
by AMC under normal conditions. The expression of MHC
II is induced under pathological and experimental conditions,
for example, these antigens are expressed when the cells are
challenged with lipopolysaccharide (LPS)[42]
or with interferon-γ (IFN-γ)[43]. MHC II expression on AMC was also
induced on the introduction of live E coli in their
vicinity[25]. The expression of these antigens on AMC under
pathological conditions suggests that they have the capability of
interacting with helper/inducer cells to mount a potential
immune response.
Other protective functions AMC in the developing brain
express transferrin receptors[32] which facilitate the
acquisition of iron needed for various functions of cells. As
transferrin receptors are also important for the proliferation of
cells, they may be involved in the differentiation and
maturation of AMC. Additionally, the presence of these receptors
on AMC may serve a protective function to sequester
excess iron for storage in pathological conditions where there
is an excessive influx of iron into the brain. In support of
this, the increased expression of transferrin receptors and
iron was reported[44] in AMC in newborn rats subjected to
hypoxia. Hypoxia/reoxygenation is known to increase the
iron content of the brain in newborn
animals[45]. Excess iron not safely sequestered in storage is hazardous as it
promotes the formation of free
radicals[46], resulting in oxidative tissue damage.
AMC in the developing brain, especially in the white
matter tracts, are also thought to promote axonal
growth[47]. Cultured microglial cells derived from neonatal rat brains and
transplanted into injured spinal cords enhanced the
regeneration and elongation of spinal cord
axons[48] indicating their involvement in axonal growth. In the developing white
matter, AMC have also been reported to function as guides
for developing axons, perhaps through the manufacture of
extracellular matrix molecules, such as
thrombospondin[49,50].
Insulin-like growth factors Insulin-like growth
factor (IGF) I and II are known to regulate the development of
the nervous system[51]. IGF-I plays an important role in
promoting cell proliferation and
differentiation[52] in the developing brain. The role of IGF II during postnatal
development of the brain is less clear. Our recent
study[53] has shown the expression of IGF-I and IGF-II in AMC. The expression
of IGF-I and IGF-II was markedly enhanced in the cells by
LPS, but was significantly suppressed with all-trans retinoic
acid (RA). From these findings, it was suggested that IGF-I
expression in AMC may be linked to the state of cell activation.
IGF-I has been shown to enhance phagocytic activity of
neutrophils in vitro when they were challenged with
E coli[54]. It was demonstrated by Inoue
et al[55] that IGF-I increased the killing capacity and phagocytosis of peritoneal
macrophages when they were activated by E
coli. IGF-I expression in AMC may also have paracrine functions, such as the
modulation of the proliferation and development of the
oligodendrocytes and myelination, as it has been considered as an
important factor for oligodendrocyte survival and
myelination[56,57]. Although the exact function of IGF-II
in the developing brain is not clear, its pattern of
association with oligodendrocytes and myelin suggests that it may also play a
role in myelination[58,59] or in the phagocytic activity of AMC.
IGF-I may also be related to the antigen-presenting function
of AMC as it is known to stimulate the proliferation of
immunocompetent cells and modulate the cellular immune
functions of neutrophils and
macrophages[60].
Nitric oxide Nitric oxide (NO) is synthesized from
L-arginine by the family of NO synthase (NOS) enzymes.
NOS from neurons and endothelial cells are constitutively
expressed enzymes, the activities of which are calcium
depend-ent. Inducible NOS (iNOS), which is
calcium-independent and NO-generated from this isoform, is known to
mediate immune functions. NO production in macrophages has
been described to have protective or destructive functions.
NO production by macrophages is stimulated by various
pathogens, such as bacteria, viruses, and
parasites[61_63] and has a role in their phagocytic
activity[64]. The overproduction of NO however has toxic effects as it leads to the
formation of toxic reactive nitrogen intermediates which can have
deleterious effects[65].
It has been reported that activated microglial cells in the
white matter may contribute to perinatal brain
injury[66] through the secretion or production of noxious substances.
NO production in the corpus callosum in response to
hypoxia was found to increase in the neonatal brain along with
iNOS expression in AMC[16,67]. In
vitro studies have shown that NO produced by AMC is highly damaging to the
oligodendrocytes resulting in their
lysis[68]. The induction of iNOS in the activated microglia contributed to tissue injury
through NO overproduction in fetal brain injury caused by
umbilical cord occlusion[69]. The sustained production of
NO endows macrophages with cytotoxic activity against
viruses, bacteria, and fungi[70]. On the other hand, NO has
suppressive effects on lymphocyte proliferation and can
damage normal host cells[70] which can be deleterious.
Glutamate receptors The weak expression of NMDA
(N-methyl-D-asparate) receptor subtype 1 (NMDAR1) was
localized in AMC in the corpus callosum in the neonatal
brain. This may facilitate the cells to be responsive to the
release of glutamate from the neighboring callosal axons
undergoing degeneration in the remodeling of the
developing brain. The expression of NMDAR1 on AMC was
enhanced in response to hypoxia[16]. This may be linked to the
elevation of extracellular glutamate in the white matter in
hypoxia/ischemia, which has been described to be possibly
due to the release from damaged
axons[71]. Excess glutamate leads to toxicity and death of oligodendrocyte
progenitors[72]. Immunostimulated microglia have been reported to enhance
the NMDA receptor-mediated excitotoxicity in part through
the expression of iNOS[73]. The expression of NMDA
receptors on microglial cells has also been reported in
excitotoxic lesions in mice[74]. Although the expression of
NMDAR1 receptors on AMC has been reported to have
detrimental effects in the developing brain, they may have a
protective role by sequestering excess glutamate released
by degenerating axons.
Inflammatory response Microglial cells play an
important role in the development of an inflammatory response in
the developing brain[75]. They are thought to cause damage
to axons and the developing oligodendrocytes by releasing
inflammatory cytokines, such as interleukin
(IL)-1β and tumor necrosis factor (TNF)-α in many pathological
condi-tions, such as hypoxic_ischemic conditions, and have been
shown to express both p55TNFαR1 and p75TNFαR2
receptors[76]. Aberrant TNF-α/p55TNFαR1 signaling in the
CNS can have a potentially major role in CNS pathologies in which
oligodendrocyte death and demyelination is a primary
pathological feature[77]. Besides their inflammatory actions,
cytokines IL-1β and TNF-α may also be involved in the
transcriptional activation of the iNOS
gene[78,79]. Microglia in the developing brain have also been shown to express the
chemokine receptor CCR5 until 2 weeks of
age[80,81]. It was proposed that CCR5 were involved in microglial recruitment
and activation during brain development and after neonatal
brain injury, such as hypoxic-ischemic injury.
Endothelins Endothelins (ET), consisting of 3 subtypes,
ET-1, ET-2, and ET-3, are multifunctional peptides produced
by a wide variety of cells under normal and pathological
conditions. Besides basal vasoconstriction, they are known
to exert mitogenic and anti-apoptotic
actions[82,83], as well as act as growth-promoting factors involved in embryonic and
fetal development[84_86]. It has been reported that
macrophages and monocytes act as a source of ET-1 production
during infection and
inflammation[87,88].
We have recently reported the expression of ET,
especially ET-1 in AMC[89]. It was further demonstrated that the
expression decreased in response to hypoxia. The
stimulation of AMC with LPS enhanced the expression of ET-1. It
was suggested that the expression of ET-1 may have
auto-crine functions, such as synthesis and secretion of
chemo-kines, including stromal derived factor-1a
(SDF-1a) and monocyte chemoattractant protein-1 (MCP-1), or paracrine
actions on the developing glial cells, neurons, and blood
vessels bearing the ET receptors.
2',3'-cyclic nucleotide 3'-phosphodiesterase
The expression of the 2',3'-cyclic nucleotide 3'-phosphodiesterase
(CNPase), a myelin-associated enzyme commonly regarded
as a selective marker for immature oligodendrocytes, was
localized in AMC in the developing rat brain from prenatal
d 18 to postnatal d 10[90]. Although the function of CNPase
in AMC is not known, it may serve a cytoskeletal role to
change the shape of the cells for migration or for the
transportation of cytoplasmic materials. It may also be involved
in the phagocytic function of AMC or in the secretion of
pro-inflammatory cytokines and growth factors by them.
CNPase may also be involved in transformation of the cells
from the early round and amoeboid shape to a ramified form
with growth.
Response to drugs
Glucocorticoids Glucocorticoids, which are potent
anti-inflammatory and immunosuppressive drugs, have been
reported to suppress the number and the phagocytic activity
of macrophages[91]. The administration of glucorticoids, such
as cortisone or dexamethasone, in postnatal rats resulted in
a substantial reduction in the number of AMC in the corpus
callosum[11,92]. The decrease in the number of AMC was
attributed to the suppression of the number of circulating
monocytes, as glucocorticoids are known to reduce their
numbers[93]. Another effect of glucocorticoids on AMC was
their premature differentiation or maturation into ramified
microglia. However, the phagocytic activity or proliferation
of AMC did not appear to be affected by glucocorticoid
treatment[92]. Dexamethasone also inhibited microglial activation
by downregulating the neurotoxic and pro-inflammatory
mediators such as NO, TNF-a, and
IL-6[94_96]. Preliminary results in our laboratory (unpublished data) demonstrated
that dexamethasone inhibited the migration of microglial
cells by suppressing the release of MCP-1, a chemokine which
regulates the migration of activated microglial cells to the
inflammatory sites in the CNS. It has been further shown
that the downregulation of MCP-1 expression in activated
microglial cells by dexamethasone was mediated via the
MKP-1-dependent inhibition of the JNK and p38 mitogen-activated
protein kinase pathways.
Chloroquine Chloroquine, an antimalarial drug with
anti-inflammatory properties, has proven to be a beneficial
therapeutic agent in certain inflammatory
disorders[97]. Chloroquine is known to exert its anti-inflammatory effect by
downregulating the synthesis of pro-inflammatory
cytokines, such as TNF-α and IL-1β[98]. It also reduces the expression
of MHC II on Kupffer cells[99]. Besides its anti-inflammatory
actions, chloroquine inhibits lysosomal degradation and
produces lysosomal changes resembling that of lysosomal
storage disease in a variety of cells, including
macrophages[100,101]. Increased vacuolation and the accumulation of
lysosomes were observed in AMC in response to the
intraperitoneal administration of chloroquine in 1-d-old rats.
This was attributed to the failure of digestion of
internalized substances. The phagocytic activity and
antigen-presenting function of AMC, however, was enhanced in
response to chloroquine as evidenced by the upregulation of
CR3 receptors and MHC I antigens[102].
Colchicine The number of AMC in the corpus
callosum of postnatal rats was reduced following colchicine
treatment[103]. It also brought about an early differentiation of
AMC into the ramified form. Colchicine is a
microtubule-disrupting drug[104,105] and is known to induce apoptosis in
different cell types. In vitro studies have shown that
macrophages assume irregular profiles following
depolymerization of microtubules by
colchicine[106]. It has been hypothesized that microtubules are important for the
secretion of lysosomal enzymes and the intracellular
degradation of materials phagocytosed by
macrophages[107]. It has also been suggested that microtubules are necessary for
the fusion of lysosomes with endosomes which must
precede intracellular digestion of phagocytosed
materials[108], whereas others have reported that intact microtubules are
not required for the lysosomal-endosomal
fusion[109]. We found that the mitotic activity of AMC was suppressed by
colchicine, but the phagocytic activity remained
unaffected[103].
All-trans retinoic acid (RA) Recently, we have shown
that the RA, a vitamin A metabolite, can suppress the
LPS/β-amyloid-induced activation of microglial cells in primary
culture by inhibiting the expression and production of
TNF-α and NO[110]. It has been further shown that RA
enhances the mRNA expression of TGF-β1, which acts as an
immunosuppressor, and RA receptor (RAR) β1, and
attenuates NF-κB translocation from the cytoplasm to the
nucleus in activated microglial cells. It has been suggested that the
inhibition of TNF-a and NO synthesis by RA in the
activated microglia is mediated via the inhibition of
NF-κB translocation, which could be caused by the
upregulation of RAR and TGF-β1 gene expression. RA
has also been shown to suppress the expression of IGF-I and IGF-II in activated
microglia, indicating that RA is effective in inhibiting the
action of a wide array of molecules specific for activated
microglia[41]. In view of these results, it was suggested that
RA could be considered a potential therapeutic agent that
may inhibit the inflammatory response of microglia in
neurodegenerative diseases.
Melatonin Melatonin, a neurohormone synthesized by
the pineal gland, is known to have immunomodulatory
actions[111,112]. In addition to its immunomodulatory actions,
melatonin has also been reported to be important for
phagocytosis under physiological
conditions[113]. AMC showed a significant increase in cell numbers and upregulation of CR3,
MHC I and MHC II, and CD4 antigens in response to
melatonin administration[114],
indicating enhanced endocytic and antigen-presenting capacity. The expression of these
receptors and antigens returned to control levels on cessation
of melatonin administration, suggesting that increased
immune potentiality of the microglial cells and its maintenance
requires the continuous action of the drug.
Toxic effects of AMC
It has been reported that microglial cells may be involved
in causing apoptosis[47] in the developing brain. Although
there is no direct evidence for this observation, microglial
cells have been identified as the source of nerve growth
factor, a pro-apoptotic agent responsible for neuronal death
in the developing eye[115].
Conclusion
Early descriptions of the function of AMC focused on
their primary role, that is, phagocytosis in the developing
brain. In light of recent voluminous findings based on the
expression of a plethora of molecules and growth factors in
these cells, multiple functional roles of these cells, such as
antigen presentation, vascular regulation, chemokine release,
modulation of proliferation, and the development of other
cells in the developing brain are proposed as summarized in
Figure 3.
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