Microglia articles by MB Graeber
(Feel free to write to me for PDFs, m.graeber@imperial.ac.uk)
Graeber MB,
Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumors. Glia
40:252-259
Abstract: Microglia have long been ignored by
neurooncologists. This has changed with the realization that
microglial cells not only occur within and around brain tumors but
also contribute significantly to the actual tumor mass, notably in
astrocytic gliomas. In addition, it has been speculated that
microglia could play a role in the defense against neoplasms of the
nervous system. However, the biological success of these tumors,
i.e., their highly malignant behavior, indicates that natural
microglial defense mechanisms do not function properly in
astrocytomas. In fact, there is evidence that microglial behavior is
controlled by tumor cells, supporting their growth and infiltration.
This unexpected "Achilles heel" of microglial immune
defense illustrates the risk of generalizing on the basis of a
single aspect of microglial biology. Microglia are highly plastic
cells, capable of exerting cytotoxic functions under conditions of
CNS infections, but not necessarily during glioma progression. Thus,
the suggestion that microglial activation through stimulation by
cytokines (e.g., interferon-gamma) will benefit patients with brain
tumors could prove fatally wrong. Therapeutic recruitment of
microglia to treat such diffusely infiltrative brain tumors as
astrocytic gliomas must be considered premature
Flugel A, Hager G, Horvat A, Spitzer C, Singer GM, Graeber
MB, Kreutzberg GW, Schwaiger FW (2001) Neuronal MCP-1 expression in
response to remote nerve injury. J.Cereb.Blood Flow Metab
21:69-76
Abstract: Direct injury of the brain is followed by
inflammatory responses regulated by cytokines and chemoattractants
secreted from resident glia and invading cells of the peripheral
immune system. In contrast, after remote lesion of the central
nervous system, exemplified here by peripheral transection or crush
of the facial and hypoglossal nerve, the locally observed
inflammatory activation is most likely triggered by the damaged
cells themselves, that is, the injured neurons. The authors
investigated the expression of the chemoattractants monocyte
chemoattractant protein MCP-1, regulation on activation normal
T-cell expressed and secreted (RANTES), and interferon-gamma
inducible protein IP10 after peripheral nerve lesion of the facial
and hypoglossal nuclei. In situ hybridization and
immunohistochemistry revealed an induction of neuronal MCP-1
expression within 6 hours postoperation, reaching a peak at 3 days
and remaining up-regulated for up to 6 weeks. MCP-1 expression was
almost exclusively confined to neurons but was also present on a few
scattered glial cells. The authors found no alterations in the level
of expression and cellular distribution of RANTES or IP10, which
were both confined to neurons. Protein expression of the MCP-1
receptor CCR2 did not change. MCP-1, expressed by astrocytes and
activated microglia, has been shown to be crucial for monocytic, or
T-cell chemoattraction, or both. Accordingly, expression of MCP-1 by
neurons and its corresponding receptor in microglia suggests that
this chemokine is involved in neuron and microglia interaction
Flugel A, Bradl M, Kreutzberg GW, Graeber
MB (2001) Transformation of donor-derived bone marrow precursors
into host microglia during autoimmune CNS inflammation and during
the retrograde response to axotomy. J.Neurosci.Res.
66:74-82
Abstract: Macrophages in the brain can have a triple
source. They may originate from recently blood-derived precursors,
from the largely resident perivascular cell population (perivascular
macrophages and related cells), and from intrinsic parenchymal as
well as perivascular microglia. Although continuous exchange of part
of the perivascular cell population with bone marrow-derived
precursors is now accepted, the turnover of adult parenchymal
microglia has remained enigmatic. Using bone-marrow chimeras
carrying an unexpressed marker gene and carbon labeling of
peripheral monocyte/macrophages in a combined model of facial nerve
axotomy and transfer experimental autoimmune encephalitis, we
demonstrate for the first time that there is an easy to induce
exchange between parenchymal central nervous system (CNS) microglia
and the macrophage precursor cell pool of the bone marrow.
Furthermore, very low level infiltration of the CNS parenchyma by
recently bone marrow-derived microglia could be observed after
simple peripheral nerve axotomy that is followed by neuronal
regeneration. Thus, microglial cells can be considered wanderers
between the peripheral immune system and the CNS where they may act
as a "Trojan horse" in infections. The fact that recently
bone marrow-derived parenchymal microglia fully integrate into a
regenerating brain nucleus' architecture encourages entirely new
approaches for delivering genes into the adult CNS
Flugel A, Labeur MS, Grasbon-Frodl EM, Kreutzberg GW, Graeber
MB (1999) Microglia only weakly present glioma antigen to cytotoxic
T cells. Int.J.Dev.Neurosci. 17:547-556
Abstract: Microglia and
brain macrophages represent a substantial fraction of the cells
present in astrocytic gliomas. Yet, the functional role of microglia
in these tumors has remained enigmatic. We have compared rat
microglial cells and thymocytes with regard to their ability to
present purified CNS proteins, MBP and S100beta, as well as C6
glioma cells to specific T lymphocytes. In addition, a new
cytotoxicity assay based on fluorescence activated cell sorting of
tumor cells carrying the green fluorescent protein was established.
This assay was used to determine the influence of microglial
population density and activational state on C6 glioma cell survival
in vitro. Microglia were consistently found to present MBP and
S100beta less efficiently than thymocytes and appeared to be unable
to present C6 glioma cells to cytotoxic T lymphocytes. In addition,
high concentrations of microglial cells attenuated the cytotoxic
effects of these T cells on C6 glioma cells whereas thymocytes
significantly supported their specific killing. It is suggested that
defense functions of microglial cells against C6 glioma are severely
compromised and that the observed deficiency in antigen presentation
may play an important role for astrocytoma growth in vivo
Egensperger R, Kosel S, von Eitzen U, Graeber
MB (1998) Microglial activation in Alzheimer disease: Association
with APOE genotype. Brain Pathol. 8:439-447
Abstract: Microglial
cells are considered to play an important role in the pathogenesis
of Alzheimer disease. Apart from producing the Alzheimer amyloid
precursor (APP) as an acute phase protein, microglial cells seem to
be involved in the deposition of its amyloidogenic cleavage product,
the amyloid-beta peptide (Abeta). Abeta is bound by apolipoprotein E
(APOE) in an isoform-specific manner, and it has been demonstrated
that inheritance of the AD susceptibility allele, APOE epsilon4, is
associated with increased deposition of Abeta in the cerebral
cortex. However, the relationship between APOE epsilon4 gene dose
and microglial activation is unknown. Using microglial expression of
major histocompatibility complex class II molecules as a marker, we
have performed a quantitative genotype-phenotype analysis on
microglial activation in frontal and temporal cortices of 20 APOE
genotyped AD brains. The number of activated microglia and the
tissue area occupied by these cells increased significantly with
APOE epsilon4 gene dose. When a model of multiple linear regression
was used to compare the relative influence of APOE genotype, sex,
disease duration, age at death, diffuse and neuritic plaques as well
as neurofibrillary tangles on microglial activation, only APOE
genotype was found to have a significant effect. Thus, the APOE gene
product represents an important determinant of microglial activity
in AD. Since microglial activation by APP has been shown to be
modulated by apoE in vitro, a direct role of microglia in AD
pathogenesis is conceivable
Eitzen U, Egensperger R, Kosel S, Grasbon-Frodl EM, Imai Y,
Bise K, Kohsaka S, Mehraein P, Graeber
MB (1998) Microglia and the development of spongiform change in
Creutzfeldt-Jakob disease. J.Neuropathol.Exp.Neurol.
57:246-256
Abstract: Recent in vitro experiments suggest that
neurotoxicity of the prion protein is dependent on the presence of
microglia. We have studied 11 cases of Creutzfeldt-Jakob disease
(CJD) using immunocytochemistry in combination with computerized
image analysis to clarify the relationship between spongiform change
and microglial activation. MHC class II-positive microglia were
almost exclusively confined to cortical gray matter where the
neuropil area occupied by these cells exceeded that of controls more
than 350-fold. In cortical regions with a bimodal distribution of
spongiform degeneration, the presence of class II-positive microglia
correlated well with the presence of vacuolation in layer V, but
significantly less with spongiform change in layers II and III. In
areas where spongiform degeneration affected the entire depth of the
cortex, activated microglia were predominantly located in the inner
one-half of the cortex or were evenly distributed throughout all
cortical laminae. Here, microglia exhibited atypical, tortuous cell
processes and occasionally intracytoplasmic vacuoles, suggesting
that microglia themselves may become a disease target. Taken
together, our results provide indirect evidence against an early
causative involvement of microglia in the development of spongiform
change. At later stages, however, diseased microglia could produce
harmful factors which mediate both astrogliosis and neuronal injury
Graeber MB,
Lopez-Redondo F, Ikoma E, Ishikawa M, Imai Y, Nakajima K, Kreutzberg
GW, Kohsaka S (1998) The microglia/macrophage response in the
neonatal rat facial nucleus following axotomy. Brain Res.
813:241-253
Abstract: Microglia represent a population of brain
macrophage precursor cells which are intrinsic to the CNS
parenchyma. Transection of the facial nerve in the newborn rat
causes death of the affected motor neurons which is accompanied by
massive activation of local microglia. Many of these cells develop
into macrophages as can be shown by immunocytochemistry for OX-42
and ED1. Using the new polyclonal microglial marker ionized calcium
binding adapter molecule 1, iba1, in combination with
immunocytochemical double-labeling for the proliferating cell
nuclear antigen (PCNA), or [3H]thymidine autoradiography, and
confocal microscopy, qualitative as well as quantitative differences
can be demonstrated between the newborn and the adult axotomized rat
facial nucleus. While microglial cells are the only cell population
which responds to axotomy by cell division in the adult facial
nucleus, GFAP positive reactive astrocytes can be shown to undergo
mitosis following axotomy in the newborn rat. Furthermore, ED1
immunoreactivity, early expression of MHC class II molecules and
morphological transformation of microglia into macrophages can only
be observed under conditions of neuronal degeneration, i.e., in the
neonatal rat facial nucleus. Thus, the combination of cellular
markers described here should be useful for studies employing the
neonatal rat facial nucleus as an in vivo assay system to test the
efficacy of neurotrophic factors
Tran CT, Wolz P, Egensperger R, Kosel S, Imai Y, Bise K,
Kohsaka S, Mehraein P, Graeber
MB (1998) Differential expression of MHC class II molecules by
microglia and neoplastic astroglia: relevance for the escape of
astrocytoma cells from immune surveillance.
Neuropathol.Appl.Neurobiol. 24:293-301
Abstract: There is
increasing evidence that microglia serve as antigen presenters in
the human CNS. Although the occurrence of MHC class II
immunoreactive cells has been reported in astrocytic gliomas, the
relative contribution of microglia to this cell population has not
been studied in detail. Using computer-assisted image analysis, we
have investigated the expression of MHC class II molecules and of
the microglia/macrophage markers Ki-MIP, RCA-1, KP1 and iba1, in 97
astrocytic gliomas comprising all WHO grades to answer the question
whether there is a correlation between tumour grade and the number
of MHC class II positive microglia/macrophage profiles. Microglia
expressing MHC class II were common in astrocytomas and anaplastic
astrocytomas but rare in pilocytic tumours although there was
significant variation within each group. MHC class II
immunoreactivity was reduced in highly cellular areas of
glioblastomas where large numbers of cells expressing macrophage
markers were still present. Thus, there was no simple relationship
between tumour grade and microglial/macrophage MHC class II
expression. In addition, up to 55% of astrocytic gliomas contained
MHC class II immunoreactive tumour cells. Microglia but not tumour
cells were found to express the BB1/B7 costimulator. We conclude
that microglia in astrocytic gliomas are well equipped to function
as antigen presenting cells. Yet, neoplastic astroglia appear to
acquire the capacity to downregulate microglial MHC class II
expression and, at the same time, may induce T-cell clonal anergy
through aberrant expression of MHC class II molecules
Jones LL, Banati RB, Graeber
MB, Bonfanti L, Raivich G, Kreutzberg GW (1997) Population control
of microglia: does apoptosis play a role? J.Neurocytol.
26:755-770
Abstract: Brain lesions, even of the most subtle type,
are accompanied by the activation of microglia, the main immune
cells of the brain. Microglial cells dramatically increase in number
through proliferation and adhere to the injured neurons, where they
displace the synaptic input. After proliferation, microglia
gradually migrate into the nearby parenchyma and appear to decrease
in number. Here we examined the possible involvement of apoptosis in
the regulation of the microglial cell number using Terminal
transferase mediated d-UTP Nick End-Labelling (TUNEL). In vitro,
cell death is a common phenomenon in microglial cell cultures, and
is enhanced by the withdrawal of the mitogen, granulocyte-macrophage
colony stimulating factor. In vivo, application of the
TUNEL-reaction revealed TUNEL-positive microglia beginning at day 4,
with a peak 7 days after transection of the facial nerve.
Surprisingly, TUNEL-labelling in vivo was localized on the outer
side of the nuclear membrane and in the microglial cytoplasm, with
very little staining within the nucleus itself. These TUNEL-labelled
cells also lacked other classic morphological signs of apoptosis,
like membrane blebbing, chromatin condensation and apoptotic bodies.
These data suggest that the regulation of post-mitotic microglia is
not mediated by the classic pathway of apoptosis
Kosel S, Egensperger R, von Eitzen U, Mehraein P, Graeber
MB (1997) On the question of apoptosis in the parkinsonian
substantia nigra. Acta Neuropathol.(Berl) 93:105-108
Abstract:
Apoptosis has been postulated as a mechanism of nerve cell death in
Parkinson's disease. In the present study, the substantia nigra of
22 neuropathologically confirmed Parkinson cases and 8 control
brains was studied using the in situ end-labeling (TUNEL) method.
About 50% of parkinsonian brains showed a small number of
TUNEL-positive glial cells in the substantia nigra, whereas no
neurons showed convincing TUNEL positivity or any morphological
signs of apoptosis. No correlation was observed between the number
of TUNEL-positive glial cells and microglial activation. Our results
fail to demonstrate apoptosis as a mechanism of cell death in
Parkinson's disease
Kosel S, Egensperger R, Bise K, Arbogast S, Mehraein P,
Graeber MB (1997)
Long-lasting perivascular accumulation of major histocompatibility
complex class II-positive lipophages in the spinal cord of stroke
patients: possible relevance for the immune privilege of the brain.
Acta Neuropathol.(Berl) 94:532-538
Abstract: Six cases of middle
cerebral artery occlusion are presented in which the cellular
changes accompanying descending degeneration of the lateral
corticospinal tract were studied at different time points (5 days-10
years) following the insult. Microglia and perivascular cells were
found to ingest large amounts of myelin degradation products, while
expressing high levels of major histocompatibility complex (MHC)
class II molecules. Activation of perivascular macrophages, as
indicated by increased class II expression, lasted for many years
and appeared to follow down-regulation of both phagocytic activity
and class II expression on parenchymal microglia. TUNEL labeling was
absent from both microglia and perivascular cells at all time points
investigated. Indirect evidence is presented that microglia may
transfer myelin degradation products to the perivascular space.
Perivascular cells which express MHC class II molecules
constitutively do not appear to leave the perivascular compartment
in large numbers and could release myelin degradation products into
the cerebrospinal fluid. The possible immunological consequences of
these findings are discussed with respect to their possible
relevance for antigen presentation and autoimmune central nervous
system disease
Streit WJ, Graeber MB (1996) Microglia: a pictorial. Prog.Histochem.Cytochem. 31:1-89
Banati RB, Graeber
MB (1994) Surveillance, intervention and cytotoxicity: is there a
protective role of microglia? Dev.Neurosci. 16:114-127
Abstract:
The study of microglial cell biology has become the key to
understanding the brain's fundamental tissue reactions as well as
the cellular mechanisms underlying CNS disease. This article focuses
on glial-neuronal interactions with special reference to human
pathology. Three important areas of brain pathology are critically
reviewed: multiple sclerosis and CNS inflammation, the brain in AIDS
and opportunistic infections, and neurodegenerative disorders.
Although microglial cytotoxicity may cause bystander damage, e.g. in
ischemia, there is little evidence to support the view that
microglial activation per se is pathogenic. Results suggesting that
one important normal function of microglia is to protect the
integrity of the central nervous system are discussed. The concept
is proposed that microglia function as a highly developed guardian
to the CNS
Graeber MB, Mehraein P (1994) Microglial rod cells. Neuropathol.Appl.Neurobiol. 20:178-180
Graeber MB (1994) Development of the microglia literature. Neuropathol.Appl.Neurobiol. 20:215-216
Graeber MB, Bise K, Mehraein P (1994) CR3/43, a marker for activated human microglia: application to diagnostic neuropathology. Neuropathol.Appl.Neurobiol. 20:406-408
Graeber MB (1993) Microglia, macrophages and the blood-brain barrier. Clin.Neuropathol. 12:296-297
Graeber MB, Bise K,
Mehraein P (1993) Synaptic stripping in the human facial nucleus.
Acta Neuropathol.(Berl) 86:179-181
Abstract: An autopsy case of
severe peripheral facial nerve paresis with disconnection of
synapses from facial motor neurons is reported. A 77-year-old man
presented with left-sided otitis media and subsequent development of
facial nerve paresis. Three months later, the patient died of an
acute gastrointestinal bleeding from a chronic duodenal ulcer. Gross
inspection of the brain revealed non-stenosing arteriosclerotic
vascular changes and a single small cystic lesion in the right
putamen. Microscopically, marked chromatolytic changes were observed
in the left facial nucleus. Immunocytochemistry for synaptophysin
revealed a marked loss of afferent synaptic contacts from somatic
and stem dendritic surface membranes of all chromatolytic motor
neurons. Wrapping of a number of neurons by newly formed glial
fibrillary acidic protein-positive astrocytic cell processes could
be detected in the regenerating facial motor nucleus. In addition,
expression of HLA-DR was increased on a small number of microglia
and perivascular cells. These changes were absent from the
contralateral, normal-appearing facial nucleus. To our knowledge,
this case provides the first evidence for disconnection of synapses
following peripheral nerve lesioning in humans. Occurrence of
synaptic stripping is likely to explain nuclear hyperexcitability
and failure of recovery of complex fine motor movements that are
commonly observed following peripheral injury to the facial nerve
Streit WJ, Graeber
MB (1993) Heterogeneity of microglial and perivascular cell
populations: insights gained from the facial nucleus paradigm. Glia
7:68-74
Abstract: We reflect here on the development of a
neuroimmunological concept which has been formulated over the past 5
years through studying microglial cell responses in the facial nerve
system. A simple axotomy of the adult rat facial nerve which causes
regeneration of facial motor neurons and little, if any, cell death
can activate microglial cells just as easily as a full-blown
degeneration of the entire nucleus induced by toxic ricin. In both
instances, the prompt microglial reaction is characterized by a
series of structural and phenotypic changes which are in many ways
similar to an immune response, e.g., there is cell proliferation and
upregulation of MHC antigens. However, since white blood cells do
not participate in the retrograde response of facial motor neurons,
we have adopted a notion which views microglia as a CNS-wide network
of immunocompetent cells whose morphological dissimilarities from
leukocytes are a result of their unique adaptation to the CNS
architecture. We have continued our in vivo investigations of the
phagocytic and immunophenotypic properties of microglial and
perivascular cells during the retrograde reaction of facial motor
neurons by using intra-neural injections of fluorogold (FG) and
ricin followed by lectin and immunostaining for microglia. Two new
findings can be added to the microglial neuroimmune network: (1)
Microglia take up FG only after motor neuron degeneration, whereas
perivascular cells may take up FG under nondegenerating conditions.
(2) Immunologically important molecules, such as MHC class II, CD4,
and leukocyte common antigens, are expressed by different microglial
subpopulations. Thus there is functional and phenotypic
heterogeneity among immunocompetent cells of the CNS
Graeber MB, Streit
WJ, Buringer D, Sparks DL, Kreutzberg GW (1992) Ultrastructural
location of major histocompatibility complex (MHC) class II positive
perivascular cells in histologically normal human brain.
J.Neuropathol.Exp.Neurol. 51:303-311
Abstract: The expression of
major histocompatibility complex (MHC) class I and II antigens was
studied in surgical and postmortem brain biopsy tissue using light
and electron microscopic immunocytochemistry. In addition,
monoclonal antibodies directed against human macrophages (EBM11) and
alpha-smooth muscle actin were applied. It is shown that blood
vessel-associated MHC class II immunoreactivity in histologically
normal human brain can be localized to a distinct class of cells,
termed perivascular cells, which share macrophage but not smooth
muscle cell antigen. This immunophenotype, the location in the
perivascular space as well as the morphology, frequency and tissue
distribution distinguish perivascular cells from pericytes and
intraparenchymal microglia. It is suggested that MHC class II
positive perivascular cells are a normal constituent of the human
cerebral microvasculature. The potential role of these cells in
immunological reactions occurring at the blood-brain interface is
discussed
Schoen SW, Graeber
MB, Kreutzberg GW (1992) 5'-Nucleotidase immunoreactivity of
perineuronal microglia responding to rat facial nerve axotomy. Glia
6:314-317
Abstract: The ecto-enzyme 5'-nucleotidase was localized
immunocytochemically in the axotomized rat facial nucleus. As
revealed by the monoclonal antibody 5N4-2,5'-nucleotidase
immunoreactivity markedly increased on perineuronal microglia during
the first week following axotomy, and gradually disappeared from
these cells by the end of the third post-operative week.
Interestingly, parenchymal microglia were not or only weakly
stained. These findings indicate that 5'-nucleotidase
5N4-2-immunoreactivity may serve as a marker for perineuronal
microglia, a population of satellite glial cells that appear to be
actively engaged in lesion-induced synaptic changes during
regeneration
Streit WJ, Graeber MB (1991) Perivascular location and phenotypic heterogeneity of microglial cells in the rat brain. J.Neuroimmunol. 33:87
Graeber MB, Streit
WJ, Kiefer R, Schoen SW, Kreutzberg GW (1990) New expression of
myelomonocytic antigens by microglia and perivascular cells
following lethal motor neuron injury. J.Neuroimmunol.
27:121-132
Abstract: The results of the present study demonstrate
that following lethal motor neuron injury microglia and perivascular
cells, as well as brain macrophages derived from the latter two cell
types, newly express antigens of the myelomonocytic lineage as
recognized by the monoclonal antibodies ED1 and ED3. It is suggested
that differences in the immunophenotype of resident brain macrophage
precursor cells, i.e. microglia and perivascular cells, and
macrophages occurring outside the central nervous system (CNS) may
be explained by differences in local macrophage antigen expression
rather than by a different embryological lineage. The new appearance
of antigens common to peripheral macrophages on neural phagocytes in
CNS lesions may therefore not necessarily imply that most or all of
these cells are of recent blood origin
Graeber MB, Streit WJ, Kreutzberg GW (1990) The third glial cell type, the microglia: cellular markers of activation in situ. Acta Histochem.Suppl 38:157-160
Graeber MB, Streit
WJ (1990) Microglia: immune network in the CNS. Brain Pathol.
1:2-5
Abstract: In recent years much progress has been made
toward a better understanding of the nature and function of
microglial cells. This review summarizes new developments and
attempts to provide a perspective for future avenues to take in
microglial research. Microglia are considered to play an active role
in a variety of neurological diseases. Their function in forming a
network of immune competent cells within the CNS is discussed
Graeber MB, Streit WJ (1990) Perivascular microglia defined. Trends Neurosci. 13:366
Graeber MB, Streit
WJ, Kreutzberg GW (1989) Formation of microglia-derived brain
macrophages is blocked by adriamycin. Acta Neuropathol.(Berl)
78:348-358
Abstract: Injection of ricin, the toxic lectin from
Ricinus communis, into the rat facial nerve leads to rapid
degeneration of motor neurons and concomitant proliferation and
transformation of endogenous microglia into brain macrophages. Using
[3H]-thymidine autoradiography, immunocytochemistry for microglial
markers and electron microscopy, we could show that when ricin was
administered together with the cytostatic drug adriamycin, the
retrogradely transported adriamycin inhibits the macrophage response
induced by toxic ricin. It is concluded that under conditions of
neuronal degeneration, e.g., following ricin intoxication, brain
macrophages are predominantly, if not exclusively, derived from
endogenous microglia
Graeber MB, Streit
WJ, Kreutzberg GW (1989) Identity of ED2-positive perivascular cells
in rat brain. J.Neurosci.Res. 22:103-106
Abstract: A
controversial, though fundamental, issue in neurobiology concerns
the nature, origin, and function of brain macrophages. By
immunocytochemical analysis using monoclonal antibodies directed
against rat macrophage antigens, i.e., ED1-3, Ox-41, Ox-42, and
Ki-M2R, we show that a group of perivascular cells located within
the basal membrane of CNS blood vessels are immunoreactive. These
cells, which resemble pericytes in terms of their anatomical
distribution, are distinct from resting parenchymal microglia
immunologically as well as morphologically. Our results demonstrate
considerable heterogeneity in the immunophenotype of resident brain
macrophages, which may be part of the immune-nervous system
interface
Graeber MB, Banati
RB, Streit WJ, Kreutzberg GW (1989) Immunophenotypic
characterization of rat brain macrophages in culture. Neurosci.Lett.
103:241-246
Abstract: Five monoclonal antibodies specific for rat
monocytes/macrophages were used to characterize
macrophages/microglia bulk isolated from neonatal and adult rat
brain. The majority of brain macrophages was positive for all
antibodies tested with minor differences between cultures derived
from developing and mature central nervous tissue. These results
contrast in vivo findings indicating that most antigens of
peripheral macrophages are absent from resting, activated and
phagocytic microglia in situ. We conclude that brain
macrophages/microglia newly express antigens of the myelomonocytic
lineage when in culture and that cultured brain macrophages may be
derived from different types of precursor cells normally present
within the CNS
Kreutzberg GW, Graeber
MB, Streit WJ (1989) Neuron-glial relationship during regeneration
of motorneurons. Metab Brain Dis. 4:81-85
Abstract: Following
axonal interruption, structural, metabolic and physiological
parameters change in motorneurons. Also, glial cells are involved in
this process. Microglia proliferate and express new proteins such as
vimentin or MHC antigens. Astrocytes show hypertrophy, increased
GFAP synthesis, and formation of lamellae. Both glial cell types
participate in deafferentation and insulation of regenerating
neurons, a process with significance for post-lesioning functional
impairment
Rieske E, Graeber
MB, Tetzlaff W, Czlonkowska A, Streit WJ, Kreutzberg GW (1989)
Microglia and microglia-derived brain macrophages in culture:
generation from axotomized rat facial nuclei, identification and
characterization in vitro. Brain Res. 492:1-14
Abstract: In order
to study microglial cells and microglia-derived brain macrophages in
vitro, a method has been developed which allows the transfer of
mitotic microglial cells from adult rat brain into tissue culture.
The studies were performed on facial motor nuclei which were
explanted after axotomy of the facial nerve. Outgrowing cells were
identified and characterized by (i) morphological criteria using
light and electron microscopy, (ii) in vivo [3H]thymidine labeling
combined with subsequent in vitro autoradiography, (iii)
immunocytochemistry for vimentin, GFAP, Fc and complement receptors,
MHC antigens, laminin, fibronectin, factor VIII related- and 04
antigen as well as lectin histochemistry, and (iv) functional in
vitro tests. In addition, a microglial cell line was established
from proliferating cells. The results indicate that perineuronal
microglia rather than astrocytes, perivascular cells,
oligodendrocytes or endothelial cells may become phagocytic after
having been activated by axotomy in situ
Streit WJ, Graeber
MB, Kreutzberg GW (1989) Peripheral nerve lesion produces increased
levels of major histocompatibility complex antigens in the central
nervous system. J.Neuroimmunol. 21:117-123
Abstract:
Proliferation of central nervous system (CNS) glia in response to
peripheral nerve injury occurs without apparent participation of
cells of the immune system. It is shown here that following
transection of the rat facial nerve there is strongly elevated
expression of class I, and to a lesser extent, class II antigens of
the major histocompatibility complex (MHC) in the facial nucleus. It
is demonstrated by double-immunofluorescence studies that the cells
responsible for increased levels of MHC class I antigens are
endogenous brain microglia. These findings emphasize the thought
that microglia are immunocompetent cells, but, at the same time,
raise the possibility for a non-immunological function of MHC
antigens under conditions of neural regeneration
Streit WJ, Graeber
MB, Kreutzberg GW (1989) Expression of Ia antigen on perivascular
and microglial cells after sublethal and lethal motor neuron injury.
Exp.Neurol. 105:115-126
Abstract: The expression of
immune-associated (MHC class II) antigen was studied
immunohistochemically over several months in the rat facial nucleus
after nerve transection and after intraneural injection of toxic
ricin. Cells expressing Ia antigen were of a perivascular type and
parenchymal ramified microglia. In the first few weeks after nerve
lesions we observed a gradual increase in the number of
Ia-immunoreactive cells starting with an initial appearance of
Ia-positive perivascular cells which were succeeded by increasing
numbers of Ia-positive ramified microglia. In long-term animals Ia
expression was almost exclusively found in microglia. We propose (a)
the existence of a population of immunocompetent perivascular cells
normally present in adult rat brain that can be stimulated to
express Ia antigen, and (b) the existence of a subpopulation of
ramified microglia that arises through transformation of Ia-positive
perivascular cells in the adult under pathological conditions
Graeber MB, Streit
WJ, Kreutzberg GW (1988) The microglial cytoskeleton: vimentin is
localized within activated cells in situ. J.Neurocytol.
17:573-580
Abstract: Unlike astrocytes and oligodendrocytes,
microglia are extremely plastic making them the chameleon among the
glial cells in the CNS. This great mutability of the microglial cell
shape suggests the presence of an elaborate cytoskeleton which is
demonstrated here by applying a new ultrastructural method. Electron
microscopic immunocytochemistry shows the presence of vimentin at
intermediate filament sites in reactive microglia stimulated by rat
facial nerve axotomy. It is suggested that vimentin-expression may
serve as a marker for activated states of microglia, including brain
macrophages
Graeber MB, Streit
WJ, Kreutzberg GW (1988) Axotomy of the rat facial nerve leads to
increased CR3 complement receptor expression by activated microglial
cells. J.Neurosci.Res. 21:18-24
Abstract: Axotomy of the rat
facial nerve leads to mitotic divisions of microglial cells without
developing into phagocytes. In order to study the functional
characteristics of those activated, i.e., proliferating but
nonphagocytic, microglia we investigated the expression of
monocyte/macrophage antigens by these cells. Our results show that
activated microglia lack monocyte/macrophage antigens recognized by
the monoclonal antibodies Ox-41, ED1, ED2, and Ki-M2R but express
high levels of CR3 complement receptors in situ
Graeber MB,
Kreutzberg GW (1988) Delayed astrocyte reaction following facial
nerve axotomy. J.Neurocytol. 17:209-220
Abstract: Transection of
the facial nerve causes a rapid increase of glial fibrillary acidic
protein in reactive astrocytes and a proliferation of local
microglial cells. The latter is associated with a detachment of
synaptic terminals from the regenerating motor neurons. About 3
weeks following axotomy the reactive astrocytes begin to form thin,
sheet-like lamellar processes which cover virtually all neuronal
surfaces. A high 5'-nucleotidase enzymic activity can be
demonstrated in the plasma membrane of these thin cell processes.
Subsequently, the lamellar processes become arranged in stacks which
persist for several months and thus isolate the regenerating motor
neurons from their afferent synaptic input. It is speculated that
the process may protect the motor neurons during regeneration
Graeber MB, Tetzlaff
W, Streit WJ, Kreutzberg GW (1988) Microglial cells but not
astrocytes undergo mitosis following rat facial nerve axotomy.
Neurosci.Lett. 85:317-321
Abstract: Transection of the facial
nerve leads to a glial response within its central nucleus of
origin. Concomitant with a proliferation of satellite microglial
cells an astrocytic reaction is also seen. In the present study
light and electron microscopic autoradiography were performed in
order to clarify whether only microglial cells undergo mitosis
following facial nerve axotomy or if astrocytes also divide. Our
results provide the first electron microscopical autoradiographic
evidence for the labelling of endogenous microglial cells. We
suggest that microglial cells are the only proliferating element
during this process in the rat facial nucleus
Streit WJ, Graeber
MB, Kreutzberg GW (1988) Functional plasticity of microglia: a
review. Glia 1:301-307
Abstract: The present review summarizes
recently acquired data in vivo, which support a role of CNS
microglia as a source of defense cells in the CNS capable of
carrying out certain immune functions autonomously. We have kept the
following discussion restricted to microglial cells and have not
included work on the immunological functions of astrocytes, which
has been recently reviewed elsewhere (Fontana et al.: Immunological
Reviews 137:3521-3527, 1987). Resting microglia are scattered
uniformly throughout the CNS forming a network of potential
immunoeffector cells, which can be activated by stimuli ranging from
peripheral nerve injury over viral infections to direct mechanical
brain trauma. The term "activated microglia" is used here
to describe proliferating cells that demonstrate changes in their
immunophenotype but have not undergone transformation into brain
macrophages. Such a transformation can be stimulated by neuronal
death but not by sublethal neuronal injury. Microglia may function
as antigen-presenting cells and may thus represent the effector cell
responsible for the recruitment of lymphocytes to the brain
resulting in an inflammatory reaction. The recent developments in
the understanding of microglial cell function may lead to a
redefinition of the often cited "immune privilege" of the
brain
Graeber MB,
Kreutzberg GW (1986) Astrocytes increase in glial fibrillary acidic
protein during retrograde changes of facial motor neurons.
J.Neurocytol. 15:363-373
Abstract: Concomitant with the
proliferation of satellite microglial cells occurring in the process
of motor neuron regeneration, an astrocytic hypertrophy is also
seen. A remarkable increase of glial fibrillary acidic protein
(GFAP) immunoreactivity is demonstrated in astrocytes of the facial
nucleus within a few days following nerve transection. The increase
of GFAP antigenicity is associated with an increased appearance of
glial filaments and astrocytic processes. We suggest that resident
protoplasmic astrocytes become involved in retrograde changes in
facial motor neurons and transform into reactive astrocytes. They
are of the fibrous type and highly positive for GFAP