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PubMed2005

Microglia in health and disease.

Microglia, one of three glial cell types in the central nervous system (CNS), play an important role as resident immunocompetent and phagocytic cells in the CNS in the event of injury and disease. It was del Rio Hortega in 1927 who determined that microglia belong a distinct glial cell type apart from astrocytes and oligodendrocytes, and since 1970s there has been wide recognition that microglia are immune effectors in the CNS that respond to pathological conditions and participate in initiation and progression of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and acquired immune deficiency syndrome dementia complex by releasing potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. There is also evidence to suggest that microglia are capable of secreting neurotrophic or neuron survival factors upon activation via inflammation or injury. It is thus timely to review current status of knowledge on biology and immunology of microglia, and consider new directions of investigation on microglia in health and disease.

Animals↗

PubMed2005

S100b counteracts effects of the neurotoxicant trimethyltin on astrocytes and microglia.

Central nervous system degenerative diseases are often characterized by an early, strong reaction of astrocytes and microglia. Both these cell types can play a double role, protecting neurons against degeneration through the synthesis and secretion of trophic factors or inducing degeneration through the secretion of toxic molecules. Therefore, we studied the effects of S100B and trimethyltin (TMT) on human astrocytes and microglia with two glial models, primary cultures of human fetal astrocytes and a microglia cell line. After treatment with 10(-5) M TMT, astrocytes showed morphological alterations associated with an increase in glial fibrillary acidic protein (GFAP) expression and changes in GFAP filament organization. Administration of S100B before TMT treatment prevented TMT-induced changes in morphology and GFAP expression. A decrease in inducible nitric oxide synthase expression was observed in astrocytes treated with TMT, whereas the same treatment induced iNOS expression in microglia. In both cases, S100B prevented TMT-induced changes. Tumor necrosis factor-alpha mRNA expression in astrocytes was not modified by TMT treatment, whereas it was increased in microglia cells. S100B pretreatment blocked the TMT-induced increase in TNF-alpha expression in microglia. To trace the mechanisms involved in S100B activity, the effect of BAY 11-7082, an inhibitor of nuclear factor-kappaB (NF-kappaB) activation, and of PD98059, an inhibitor of MEK-ERK1/2, were investigated. Results showed that the protective effects of S100B against TMT toxicity in astrocytes depend on NF-kappaB, but not on ERK1/2 activation. These results might help in understanding the role played by glial cells in brain injury after exposure to chemical neurotoxicants and support the view that S100B may protect brain cells in case of injury. (c) 2005 Wiley-Liss, Inc.

Astrocytes↗

PubMed2006

Unconjugated bilirubin activates and damages microglia.

Microglia are the resident immune cells of the brain and are the principal source of cytokines produced during central nervous system inflammation. We have previously shown that increased levels of unconjugated bilirubin (UCB), which can be detrimental to the central nervous system during neonatal life, induce the secretion of inflammatory cytokines and glutamate by astrocytes. Nevertheless, the effect of UCB on microglia has never been investigated. Hence, the main goal of the present study was to evaluate whether UCB leads to microglial activation and to the release of the cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. Additionally, we investigated the effects of UCB on glutamate efflux and cell death. The results showed that UCB induces morphological changes characteristic of activated microglia and the release of high levels of TNF-alpha, IL-1beta, and IL-6 in a concentration-dependent manner. In addition, UCB triggered extracellular accumulation of glutamate and an increased cell death by apoptosis and necrosis. These results demonstrate, for the first time, that UCB is toxic to microglial cells and point to microglia as an important target of UCB in the central nervous system. Moreover, they suggest that UCB-induced cytokine production, by mediating cell injury, can further contribute to exacerbate neurototoxicity. Interestingly, microglia cells are much more responsive to UCB than astrocytes. Collectively, these data indicate that microglia may play an important role in the pathogenesis of encephalopathy during severe hyperbilirubinemia.

Animals↗

PubMed2002

Parenchymal microglia of naïve adult C57BL/6J mice express high levels of B7.1, B7.2, and MHC class II.

In this study, we addressed B7.1, B7.2, and MHC class II expression on microglia of normal adult C57BL/6J mice, which are susceptible to MOG35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE). We showed that there are two distinct major populations of CD11b(+) cells in the central nervous system (CNS) of naïve mice: CD45 low (CD45(lo); parenchymal microglia) and CD45 intermediate (CD45(int); CNS-associated macrophages). These two populations compose CNS microglia. There is a rare CD45 high (CD45(hi)) population. By contrast, splenic CD11b(+) cells (macrophages) are CD45(int) and CD45(hi), but rarely CD45(lo). CD45(lo)CD11b(+) cells constitutively express much higher levels of B7.1, B7.2, and MHC class II compared to CD45(int) CD11b(+) cells. A shift of CD11b(+) cells from CD45(lo) to CD45(int) was observed in the CNS of EAE mice. Our study provides evidence that (1) CD45(lo) and CD45(hi), but not CD45(int), could be unique markers to differentiate parenchymal microglia from infiltrating macrophages in EAE; (2) the level of CD45 expression on parenchymal microglia (CD45(lo)) was upregulated in EAE; and (3) parenchymal microglia in normal CNS could be potent APCs by expressing high levels of B7.1, B7.2, and MHC class II molecules and could therefore play an important role in inflammation and autoimmunity in the CNS.

Animals↗

PubMed1998

Rat microglia exhibit increased density on Alzheimer's plaques in vitro.

The relationship of microglia to senile plaques was investigated by culturing glial cells derived from neonatal rat brain on cryostat sections of Alzheimer's disease (AD) or control brain. Rat microglia were identified by their uptake of DiI-acetylated LDL. Plaques were colocalized using Thioflavin-S staining. Although the number of microglia attached to AD tissue sections did not differ significantly from the number on control brain tissue, the density of microglia on senile plaques was significantly greater than on nonsenile plaque areas of the same sections. These results suggest that microglia may have a higher affinity for senile plaques than for nonsenile plaque regions of AD brain tissue and are consistent with the hypothesis that microglia respond to plaques.

Aged↗

PubMed2000

Complement component C1q modulates the phagocytosis of Abeta by microglia.

Recent studies showing that microglia internalize the amyloid beta-peptide (Abeta) suggest that these cells have the potential for clearing Abeta deposits in Alzheimer's disease, and mechanisms that regulate the removal of Abeta may therefore be of clinical interest. Previous studies from this laboratory showing that C1q enhances phagocytosis of cellular targets by rat microglia prompted the current investigations characterizing the effects of C1q on microglial phagocytosis of Abeta. Microglia were shown to phagocytose Abeta1-42, in agreement with observations of other investigators. Uptake of Abeta1-42 was observed for concentrations of 5-50 microM, and phagocytosis of peptides containing (14)C or fluorescein (FM) labels was not affected by the interaction of microglia with C1q-coated surfaces. However, inclusion of C1q (125 nM-1.4 microM) in solutions of 50 microM Abeta1-42 inhibited the uptake of (14)C-Abeta1-42 and FM-Abeta1-42, suggesting that C1q blocks the interaction of Abeta with microglia. Uptake of Abeta was partially blocked by the scavenger receptor ligands polyinosinic acid and maleylated BSA. Inhibition of Abeta uptake by C1q may contribute to the accumulation of fibrillar, C1q-containing plaques that occurs in parallel with disease progression. These data suggest that mechanisms which interfere with the binding of C1q to Abeta may be of therapeutic value both through inhibition of the inflammatory events resulting from complement activation and via altered access of Abeta sites necessary for ingestion by microglia.

Alzheimer Disease↗

PubMed2002

Glucocorticoid exacerbation of gp120 neurotoxicity: role of microglia.

Gp120 protein, part of the HIV coat, may be a causative agent in AIDS-Related Dementia (ARD) because of its demonstrated neurotoxicity in vitro and in vivo. There are two possible mechanisms for this toxicity, namely through release of toxins from the microglia or through direct action on neuronal chemokine receptors. In tissue culture, glucocorticoids (GCs), the adrenal steroids released during stress, exacerbate gp120 neurotoxicity. In this paper, we examine the means by which GCs may increase toxicity, focusing on interactions with microglia and glia. Media from microglia treated with gp120 was toxic to neurons but not to glia. The effects of GCs upon the extent of gp120-induced release of toxins by microglia seemed to be dependent on the time of exposure to the hormone. Twenty-four-hour exposure of microglia to GCs decreased the toxicity of gp120-treated microglial conditioned media. In contrast, longer-term GC exposure enhanced neurotoxicity. There also appeared to be a component of gp120 neurotoxicity in hippocampal cultures that was exacerbated by GCs, independent of the amount of microglia present. Thus, GCs appear to act at a number of different sites in the multi-cellular pathway to exacerbate the neurotoxic effects of gp120.

Animals↗

PubMed2002

Purinergic (P2X7) receptor activation of microglia induces cell death via an interleukin-1-independent mechanism.

Activation of purinergic P2X7 receptors, principally by extracellular ATP, promotes the processing and release of the cytokine interleukin-1beta (IL-1beta) and induces cell death in activated microglia and macrophages. The objective of this study was to determine if IL-1beta release contributes directly to this cell death in microglia. Exposure of microglia to bacterial lipopolysaccharide (LPS) and ATP induced release of IL-1beta and IL-1alpha, as well as cell death. Neither cell death nor IL-1 release was observed in microglia lacking the P2X7 receptor. Microglia from mice lacking the IL-1beta gene demonstrated a profile of death identical to that of wild-type microglia in response to LPS and ATP. Thus, IL-1beta is not required for P2X7 receptor-stimulated microglial death.

Adenosine Triphosphate↗

PubMed1998

A prion protein fragment primes type 1 astrocytes to proliferation signals from microglia.

Giliosis is a hallmark of prion disease. A neurotoxic prion peptide (PrP106-126) induces astrocyte proliferation in the presence of microglia. This peptide also directly enhances microglial proliferation in culture. We have investigated this further to understand the method by which factors released by microglia and PrP106-126 work together to enhance astrocyte proliferation. PrP106-126 in the presence of microglia specifically enhanced type 1 astrocyte proliferation but not Type 2. Astrocytes that do not express the prion protein were more sensitive to oxidative stress and the toxicity of cytosine arabinoside. In the presence of cytosine arabinoside, PrP106-126 was toxic to pure astrocyte cultures. Using conditioned medium from microglia we have shown that PrPc-expressing astrocytes proliferate in response to factors released by microglia stimulated by granulocyte/macrophage colony-stimulating factor. This response is enhanced in the presence of PrP106-126. PrPc-deficient astrocytes do not show this response. These results suggest that astrocytes are primed by PrP106-126 to respond more to factors released by proliferating microglia. Astrocytes may proliferate in this system to escape entering the cell suicide pathway.

Animals↗

PubMed1995

Immunophenotypic evidence for distinct populations of microglia in the rat hypothalamo-neurohypophysial system.

The morphology, distribution and immunophenotype of microglia throughout the adult rat hypothalamo-neurohypophysial system was examined. Four macrophage-associated antibodies (OX-42, F4/80, ED1 and ED2) were used; the expression of major histocompatibility complex antigens was investigated by use of antibodies against OX-6, OX-17 (MHC class II) and OX-18 (MHC class I). Three distinct types of microglia were identified. The first was located in the magnocellular nuclei; these 'radially branched' ('ramified') microglia had round cell bodies and long branched processes, and were strongly immunoreactive only for OX-42. The second was located outside the blood-brain barrier in the median eminence, pituitary stalk and neurohypophysis often close to blood vessels; these 'compact' microglia had irregular cell bodies and shorter processes, and were strongly labelled by OX-42 and F4/80, weakly labelled by OX-18, and generally unlabelled by ED1, ED2, OX-6 and OX-17. The third type was found in small numbers throughout the system at the surface of the nervous tissue or around blood vessels; these 'perivascular' microglia were elongated cells with no branching processes, and were strongly labelled by ED1, ED2, OX-18, OX-6, OX-17 and F4/80 antibodies but showed variable OX-42 immunoreactivity. Cells in a perivascular location were heterogeneous with respect to their immunophenotype. The presence in the normal adult rat hypothalamo-neurohypophysial system of MHC class-II molecules (OX-6 and OX-17) on a sub-set of perivascular microglia suggests that these cells are capable of presenting antigen to T lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Species differences in the generation of reactive oxygen species by microglia.

Although a variety of potential sources for reactive oxygen species (ROS) exist in the CNS, brain macrophages, i.e., the microglia, generate large quantities of these reactive species, particularly in response to injury or inflammatory signals. In order to understand how microglia contribute to changes in oxidative status of the CNS and how this might related to disease states, such as Alzheimer disease (AD), we have examined the regulation of superoxide anion and nitric oxide production from rodent and human microglia. Our results indicate that microglia from all species we have studied release superoxide anion, but produce significantly different amounts in response to the same activating agents. Species differences are also found in the ability to generate nitric oxide (NO). In particular, mouse microglia generate large quantities of NO when stimulated, but human and hamster microglia do not produce measurable amounts under the same stimulation conditions. These species differences are important to consider when modeling human disease processes from rodent studies.

Animals↗

PubMed2006

Aging-related changes of microglia and astrocytes in hypothalamus after intraperitoneal injection of hypertonic saline in rats.

To examine the aging-related changes of microglia and astrocytes in hypothalamus of rats after intraperitoneal injection of hypertonic saline in rats, old- and young-aged rats were injected with hypertonic saline solution into peritoneal cavity. Lectin histochemical techniques using Ricinus communis agglutinin-1 (RCA-1) and immunocytochemical method employing antibody against glial fibrillary acidic protein (GFAP) were used to demonstrate microglia and astrocytes in the hypothalamus of the rats, and the positively-stained cells were analyzed by computer-assisted image analysis system. Our results showed that the numbers of microglia and astrocytes were significantly increased in the hypothalamus of old-aged rats. After intraperitoneal injection of hypertonic saline, the number of microglia was significantly decreased in the hypothalamus of both young- and old-aged groups. After introperitoneal injection of hypertonic saline, the number of GFAP positive cells was significantly increased in the hypothalamus of young rats, but the number of GFAP positive cells did not show significant change in the hypothalamus of old rats. It is concluded that in the hypothalamus of old-aged rats, the increase of microglia may be related with the aging or degeneration of neurons, and the increase of astrocytes may provide more nourishment required by the aged neurons. The microglia and astrocytes in the hypothalamus of the two group rats may be affected by hypertonic saline, and the response of these cells to the stimuli is characterized by some aging-related changes.

Aging↗

PubMed1999

Studies of lectin receptors of rat microglia in culture: receptor distribution and internalization.

The present study examined the lectin labeling of diverse morphological forms of microglia in culture. Similar to amoeboid microglial cells in vivo, polymorphic microglia showed lectin labeling at their plasma membranes, as well as in a few cytoplasmic vesicles and vacuoles. This labeling pattern was observed in cultured microglia incubated with isolectin at 4 degrees C for 30 min. Five minutes after the temperature was raised to 37 degrees C, the surface lectin receptors appeared to be internalized, as shown by the occurrence of many subsurface lectin-labeled vesicles, vacuoles and tubule-like structures. With longer incubation (up to 1-2 h at 37 degrees C), many lysosomes and a few trans-Golgi saccules and associated lysosome-like structures became labeled. Concomitant with these changes was a reduction of lectin labeling at the plasma, with labeling having vanished in most of the cells after 1-2 h of incubation. By 24 h, only a few cells retained surface lectin labeling. It appears, therefore, that irrespective of morphology, lectin labeling (including its intracellular pathway) of microglia in culture parallels that of amoeboid microglia in vivo. This would offer a useful model for the study of lectin turnover in microglia and help to explain the roles of such receptors in microglial differentiation and function.

Animals↗

PubMed2001

Increased microglia proliferation separates pilocytic astrocytomas from diffuse astrocytomas: a double labeling study.

It is not known how many non-tumorous cells in gliomas contribute to the proliferation rate. We investigated the proliferative activity of microglia in an immunohistochemical double-labeling study of pilocytic astrocytomas and astrocytomas WHO grade II-IV using the antibodies MIB-1 (Ki67) as proliferation-marker and Ki-M1P (CD68) as microglia marker. We found the highest indices of proliferating microglia in pilocytic astrocytomas with an average rate of 32% (+/- 6.8) of all proliferating cells. In contrast, the proliferation indices of microglia were lowest in fibrillary astrocytomas with 8.6% (+/- 2.5) of all proliferating cells. In anaplastic astrocytomas and glioblastomas the percentage of proliferating microglia showed a slight increase to 8.8% (+/- 3.6) and 13.4% (+/- 8.7), respectively. We conclude that microglial cells in astrocytic brain tumors proliferate and show different proliferative activities at different grades of malignancy with the highest rates of proliferating microglia especially in pilocytic astrocytomas. Thus, the proliferation rate does not solely reflect the proliferation of tumor cells, but also of non-tumorous cells. This should be considered in particular when proliferation rates are used as a criterion for prognosis and grading of pilocytic astrocytomas.

Antigens, CD↗

PubMed2006

Purinoceptors in microglia and neuropathic pain.

Emerging evidence indicates that microglia play a critical role in the pathogenesis of neuropathic pain, a debilitating chronic pain condition that can occur after peripheral nerve damage caused by disease, infection, or physical injury. Microglia are immunocompetent cells of the central nervous system and express various ionotropic P2X and metabotropic P2Y purinoceptors. After injury to a peripheral nerve, microglia in the spinal cord become activated and upregulate expression of the P2X4 receptor. Recent findings suggest that activation of P2X4 receptors evokes release of brain-derived neurotrophic factor from microglia and that this mediates microglia-neuron signaling leading to pain hypersensitivity. Thus, P2X4 receptors and the intracellular signaling mediators in microglia are promising therapeutic targets for the development of novel pharmacological agents in the management of neuropathic pain.

Animals↗

PubMed1996

Development of microglia and macrophages in the postnatal rat pituitary.

Microglia and macrophages, immunolabelled with F4/80 (which binds a 160-kDa plasmalemmal glycoprotein) and OX-42 (which labels the complement type 3 receptor, CR3), were identified in the neuro- and adenohypophyses, respectively, of postnatal rats from day 1 to adulthood. In the neurohypophysis, the numerical density (cells/mm2) of microglia increased from postnatal day 1 to day 7 but was then unchanged from the adult density. In the adenohypophysis, the numerical density of macrophages increased from postnatal day 1 to day 21. The increasing size of the pituitary meant that the total number of such cells increased rapidly in the neurohypophysis up to day 14, but was then essentially unchanged; in the adenohypophysis macrophages increased in proportion to the increasing size of the gland up to day 21. Proliferation of the mononuclear cells was analysed by the immunodetection of bromodeoxyuridine incorporation into the nuclei of microglia and macrophages. F4/80-immunoreactive cells incorporating bromodeoxyuridine were found on all the postnatal days studied. The proportion of such cells in the neurohypophysis was high from postnatal day 1 to day 14 and in the adenohypophysis was maximal on day 14, decreasing in both parts of the pituitary by day 21. The estimated total number of proliferating cells was maximal in both parts of the pituitary on day 14. In both parts, OX-42-immunoreactive cells were less numerous than F4/80-immunoreactive cells up to postnatal day 14; CR3 expression may therefore be associated with maturation of these cells. Neurohypophysial microglia increased in size to postnatal day 7, consistent with the assumption of a 'compact' microglial morphology; adenohypophysial macrophages did not change in size over the postnatal period. Throughout the period studied, neurohypophysial microglia were significantly more densely distributed and larger in size than adenohypophysial macrophages. Neurohypophysial microglia phagocytose terminals of neurosecretory neurons from day 7, concurrent with the development of a distinct perivascular space. In the adenohypophysis, the perivascular space was present from birth and macrophages were not phagocytic. There are, therefore, considerable differences in the density, morphology and activity between the populations of myelomonocytic cells in the postnatal rat neuro- and adenohypophyses.

Animals↗

PubMed1993

Carbachol increases intracellular free calcium in cultured rat microglia.

Microglia are resident macrophages in the CNS and have been shown to exhibit immune system responses common to other macrophages, including phagocytosis, secretion of superoxide anions, and secretion of regulatory and trophic factors such as interleukin-1. Phagocytosis and oxidative burst by macrophages are often reported to be preceded by an increase in cytosolic free calcium. In addition, a variety of compounds, including neuroactive peptides, have been shown to elicit such calcium responses in various macrophage preparations. The results presented demonstrate that cultured rat microglia respond to exposure to carbachol with an increase in intracellular free calcium which is atropine-sensitive and the result of the release of calcium from intracellular stores. Norepinephrine also induced increases in free calcium, whereas the metabotropic glutamate agonist 1S,3R-ACPD, serotonin, adenosine and ATP did not. These results suggest that microglia can respond to select neurotransmitters, and that there may exist a signaling loop between neurons and microglia. Furthermore, since cholinergic fibers have been shown to infiltrate neuritic plaques in Alzheimer's disease (AD) and microglia have been reported to be activated in plaques, these results suggest that interactions between select neurotransmitters and microglia may play a key role in neurodegenerative diseases.

Animals↗

PubMed1994

Microglia in the rat neurohypophysis increase expression of class I major histocompatibility antigens following central nervous system injury.

An immunocytochemical study of the expression of major histocompatibility complex (MHC) class I and II antigens by glial cells of the rat neurohypophysis was performed. Numerous cells with the appearance of microglia were found to constitutively express class I MHC antigens, while only rare cells expressed class II (Ia) antigens. Stereological analysis revealed that expression of class I MHC antigens increased significantly within 10 days after a unilateral hypothalamic lesion known to cause axonal degeneration and compensatory collateral axonal sprouting within the neurohypophysis. In addition, however, a brain lesion which did not affect the axonal population of the neurohypophysis also produced a significant increase in microglial expression of class I MHC antigens in this structure. Neither lesion affected the expression of class II MHC antigens in the neurohypophysis. Simultaneous immunofluorescent labeling for MHC I antigens and glial fibrillary acidic protein (GFAP, a pituicyte marker) or for MHC I and the C3bi complement receptor (a microglial marker) confirmed that the MHC class I-reactive cells were microglia. MHC I-positive cells also bound Griffonia simplicifolia B4 isolectin (GSA I-B4), consistent with their identification as microglia. The majority of MHC class I-reactive microglia were located in close apposition to blood vessels. These results indicate that an unusually large proportion of microglia within the neurohypophysis constitutively express MHC I antigens. In addition, neurohypophysial microglia are capable of responding to penetrating brain injury by upregulation of MHC I antigens in the absence of local tissue degeneration, possibly because of the absence of a blood-brain barrier.

Animals↗