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At least 685 records · Page 38Linked to original sources
PubMed1996

A neurotoxic prion protein fragment enhances proliferation of microglia but not astrocytes in culture.

The scrapie isoform of the prion protein (PrPSc) induces pathological changes in the central nervous system including neurodegeneration and gliosis. A synthetic prion protein (PrP) peptide corresponding to amino acid residues 106-126 has been shown to be toxic to neurons that express PrPC, the cellular isoform of PrP. Here we show that in mixed glial cultures PrP106-126 induces astroglial proliferation that is dependent on cellular PrPc expression. In purified cultures of glial subtypes only microglia proliferated in response to PrP106-126. This effect was independent of PrP expression. Destruction of microglia in mixed glial cultures by L-leucine methyl ester (LLME) treatment abolished enhanced proliferation caused by PrP106-126. This proliferative effect can be restored by co-culturing LLME-treated astrocytes with microglia. Microglia therefore seem to mediate the proliferative effect exerted by PrP106-126 on astrocytes.

Amino Acid Sequence↗
PubMed1997

Albumin enhances superoxide production in cultured microglia.

Microglial activation and disruption of blood-brain barrier (BBB) are known to occur and contribute to neuronal damages in cerebral ischemic conditions and in some neurodegenerative diseases. To investigate whether a serum factor leaked out from circulation enhances microglial activation, we examined the effect of normal rat serum on superoxide (O2-) production by cultured microglia. Microglia cultured from neonatal rat brains were studied on their O2- production induced by the addition of phorbol myristate acetate by a method of acetyl-cytochrome c reduction. The O2- production was significantly increased by the addition of 0.01% rat serum, and the maximal enhancement was observed at about 0.1% rat serum. After the serum was fractionated using a molecular sieve membrane, we observed the enhancing effect only in a greater molecular weight fraction (>50 kDa). Furthermore, three kinds of bovine serum albumin (BSA) with different purity, and human serum and plasma albumins, also enhanced O2- production to a similar extent to that by rat serum. However, other proteins tested showed no significant effect. The enhancement of O2- production by BSA was observed dose-dependently, and the effect of 50 microg/ml of purified BSA was equivalent to that of 0.1% rat serum, suggesting that albumin itself enhances O2- production by microglia. These results imply that albumin leaked out through impaired BBB may activate microglia and that the potentiation of O2- production by albumin results in the pathogenesis of neuronal damage in cerebral ischemia and some neurodegenerative diseases.

Albumins↗
PubMed1998

Neurotrophins regulate the function of cultured microglia.

Although the physiological role of neurotrophins in neuronal development and survival has been extensively investigated, their role in glial cell physiology remains to be elucidated. In the present study, we investigated the effects of neurotrophins on cultured microglia from newborn rat brain. All of the neurotrophins tested nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), increased the secretion of plasminogen and urokinase type-plasminogen activator and specific activity of acid phosphatase, but suppressed the release of constitutively-produced and lipopolysaccharide-stimulated nitric oxide (NO) from microglia. The reverse transcription-polymerase chain reaction, immunocytochemical staining, and Western blotting revealed that cultured microglia express Trk A, B, and C, and low-affinity NGF receptor, LNGFRp75. Neurotrophin was found to phosphorylate Trk A and B, and the neurotrophin-induced enhancement of plasminogen-secretion was suppressed by protein kinase inhibitor, K252a. Furthermore, neurotrophins caused an activation of transcription factor, NF-kappaB. These results indicate that the neurotrophin family regulate the function of microglia through Trk and/or LNGFRp75-mediated signal transduction.

5'-Nucleotidase↗
PubMed1999

Regulation of gelatinases in microglia and astrocyte cell cultures by plant lectins.

The effects of 25 recently discovered plant lectins on cell proliferation and enzyme release were compared to those of previously known lectins on rat microglia and astrocyte cell cultures. A dose-dependent proliferation of microglial cells, but not of astrocytes, was induced by seven lectins, whereas five lectins showed dose-dependent cytotoxicity on both microglia and astrocyte cell cultures. The activity of gelatinase B (MMP-9) was strongly increased in microglial cells by the aforementioned seven lectins, by concanavalin A, and by phytohemagglutinin (PHA-E4), whereas gelatinase A (MMP-2) remained at constitutive levels. The five cytotoxic lectins decreased the activity of gelatinase B in microglia and of gelatinase A in astrocytes, in a dose-dependent manner. The lectin wheat germ agglutinin induced a decrease in gelatinase B activity in microglia, but stimulated gelatinase A and B activity in astrocytes. These results indicate that lectins possess neuromodulatory effects that may motivate the study of their effects on central nervous system (CNS) function in vivo. This, in turn, may lead to better insight into whether lectin or lectin-like molecules can interact with glial cells, and whether they have a role in acute toxicity and in multifactorial diseases in which environmental factors may play a role.

Animals↗
PubMed2000

Effects of lipopolysaccharide on oligodendrocyte progenitor cells are mediated by astrocytes and microglia.

Oligodendrocytes are the primary cells injured in periventricular leukomalacia (PVL), a predominant form of brain white matter lesion in preterm infants. To explore the possible linkage between white matter injury and maternal infection, purified rat O-2A progenitor (Oligodendrocyte-type 2 astrocyte progenitor) cell cultures were used as a model in studying the effects of lipopolysaccharide (LPS), an endotoxin, on survival and differentiation of oligodendrocytes and the involvement of other glial cells in the effects of LPS. O-2A progenitor cells were cultured from optic nerves of 7-day-old rat pups in a chemically defined medium (CDM). Astrocyte and microglia cell cultures were prepared from the cortex of 1-day-old rat brains in the CDM. Direct treatment of LPS (1 microg/ml) to O-2A cells had no effect on viability or differentiation of these cells. When O-2A progenitor cells were cultured in the conditioned medium obtained from either astrocyte or microglial cell cultures for 48 hr, survival rate and differentiation of O-2A cells into mature oligodendrocytes were greatly enhanced as measured by the MTT assay and immunocytochemistry. The conditioned medium obtained from astrocytes or microglia treated with LPS for 48 hr, however, failed to show such a promotional effect on viability and differentiation of O-2A cells. When 5 microg/ml LPS was used to stimulate astrocytes or microglia, the conditioned medium from these glial cell cultures caused O-2A cell injury. The overall results indicate that astrocytes and microglia may promote viability and differentiation of O-2A progenitor cells under physiological conditions, but they may also mediate cytotoxic effects of LPS on oligodendrocytes under an infectious disease biochemical environment.

Animals↗
PubMed2005

Mouse brain IgG-like immunoreactivity: strain-specific occurrence in microglia and biochemical identification of IgG.

Unlike the brains of most mammals, the mouse brain appears unique in the massive appearance of cells showing IgG-like immunoreactivity, which has repeatedly been shown via immunohistochemistry. In the present study, we first examined possible species differences in IgG-like immunohistochemical staining in the brains of various rodents, including mice. In four of six mouse strains examined (ICR, Balb/c, C57BL/6, and AKR/J), antibodies against mouse IgG revealed positive staining in many brain microglia. However, no such positive staining was detected in brains of the rat, hamster, guinea pig, or two other mouse strains (CBA/N and CBA/J). We purified IgG-like-immunoreactive molecule(s) biochemically from brain of the ICR mouse as a representative mouse strain. Our amino-acid-sequence analysis proved that the purified protein was identical to serum IgG. The possibility of IgG synthesis by brain microglia in the ICR mouse was denied by our RT-PCR experiments and in situ hybridization histochemistry. In addition, Fcgamma-receptor-deficient double-knockout mice of the C57BL/6 genetic background contained no IgG-immunoreactive microglia in the brain. These results clearly indicate that microglial IgG staining is due to the uptake of serum IgG through Fcgamma receptors. However, the strain-specific mechanisms resulting in microglial IgG uptake remain to be elucidated, in that Fcgamma receptors are omnipresent in microglia of all rodents examined here.

Animals↗
PubMed1994

Microglia in the avian retina: immunocytochemical demonstration in the adult quail.

Immunocytochemical techniques were used in conjunction with the QH1 antibody to study the morphological characteristics and distribution of microglia in the avascular retina of an avian species (the quail). The majority of microglial cells appeared in the outer and inner plexiform layers throughout the entire retina, whereas a few microglial cells in the nerve fiber layer were seen only in the central zone of the retina, near the optic nerve head. In the outer plexiform layer, microglial cells were star-shaped, with processes that ramified profusely in the horizontal plane. Fine process tips extended outward radially, insinuating themselves among the photoreceptors. A regular mosaic-like arrangement of microglial cells was evident in the outer plexiform layer, with no overlapping between adjacent cell territories. Microglial cells in the inner plexiform layer ramified through the entire width of this layer, showing radial and horizontal processes. Microglia in the inner plexiform layer also tended to be regularly distributed in a mosaic-like fashion, although there was slight overlapping between adjacent cell territories. Microglia density in this layer was approximately twice that in the outer plexiform layer. This pattern of microglial distribution was similar to that described in vascular retinae of several species of mammals, a finding that suggest that blood vessels are not responsible for the final locations of microglia in the adult retina, and that microglial precursors must migrate through long distances before they reach their precise destination.

Animals↗
PubMed1995

Macrophages, microglia, and astrocytes are rapidly activated after crush injury of the goldfish optic nerve: a light and electron microscopic analysis.

Several matrix and adhesion molecules in fish optic nerve, which are constitutively expressed, are increased during axonal regeneration and are primarily associated with nonneuronal cells (W.P. Battisti, Y. Shinar, M. Schwartz, P. Levitt, and M. Murray [1992] J. Neurocytol. 21:557-573). The current study examines the reactions of specific cell types to optic nerve crush and axonal regeneration. The goldfish optic nerve contains macroglia and microglia as well as a population of monocyte-derived cells (granular macrophages) unique to goldfish. Two cell types were OX-42 positive (granular macrophages and microglia), indicating monocyte lineage, each with a distinct morphology and distribution within the nerve. Within hours of the optic nerve crush, the number of OX-42-labeled cell profiles increased near the crush site, remained elevated during the time axons were elongating, and then declined. Microglia, but not granular macrophages, were phagocytically active. Astrocytes are readily identified in the normal optic nerve, but they exhibited marked morphologic changes within hours of injury, which is consistent with the contribution these cells make to the altered environment. Oligodendroglia could not be reliably identified in regenerating optic nerves until myelin was formed. A comparison of the distribution of OX-42-labeled cells with that of transforming growth factor beta-1 (TGF-beta 1) and tenascin suggests that these molecules are expressed by granular macrophages. Tenascin staining may be additionally associated with astrocytes and/or microglia. The rapid response of these nonneuronal cells to injury, their rapid phagocytic activity, and the secretion of growth-promoting factors by these cells likely contributes to the environment that supports robust regeneration by optic axons in the goldfish.

Animals↗
PubMed2005

TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway.

In acute experimental autoimmune encephalomyelitis (EAE), demyelination is induced by myelin-specific CD4(+) T lymphocytes and myelin-specific antibodies. Recovery from the disease is initiated by cytokines which suppress T cell expansion and the production of myelin-toxic molecules by macrophages. Th2/3 cell-derived signals may also be involved in central nervous system (CNS) repair. Remyelination is thought to be initiated by the recruitment and differentiation of oligodendrocyte precursor cells (OPC) in demyelinated CNS lesions. Here, we report that unlike Th1 cytokines (TNF-alpha, IFN-gamma), the Th2/3 cytokine TGF-beta induces primary microglia from C57BL/6 mice to secrete a chemotactic factor for primary OPC. We identified this factor to be the hepatocyte growth factor (HGF). Our studies show that TGF-beta-1-2-3 as well as IFN-beta induce HGF secretion by microglia and that antibodies to the HGF receptor c-Met abrogate OPC chemotaxis induced by TGF-beta2-treated microglia. In addition we show spinal cord lesions in EAE induced in SJL/J mice to contain both OPC and HGF producing macrophages in the recovery phase, but not in the acute stage of disease. Taken these findings, TGF-beta may play a pivotal role in remyelination by inducing microglia to release HGF which is both a chemotactic and differentiation factor for OPC.

Animals↗
PubMed2002

GM-CSF and M-CSF modulate beta-chemokine and HIV-1 expression in microglia.

Significant numbers of patients with acquired immunodeficiency syndrome (AIDS) develop CNS infection primarily in macrophages and microglial cells. Therefore, the regulation of human immunodeficiency virus type 1 (HIV-1) infection and activation of the brain mononuclear phagocytes subsequent to infection are important areas of investigation. In the current report, we studied the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) in the expression of antiviral beta-chemokines and HIV-1 p24 in cultures of primary human fetal microglia. We found that stimulation with GM-CSF or M-CSF induced macrophage inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented RANTES expression, after HIV-1 infection of microglia. This was not due to the effect of GM-CSF on viral expression because GM-CSF was neither necessary nor stimulatory for viral infection, nor did GM-CSF enhance the expression of env-pseudotyped reporter viruses. Blocking GM-CSF-induced microglial proliferation by nocodazole had no effect on beta-chemokine or p24 expression. The functional significance of the GM-CSF-induced beta-chemokines was suggested by the finding that, in the presence of GM-CSF, exogenous beta-chemokines lost their anti-HIV-1 effects. We further show that although HIV-1-infected microglia produced M-CSF, they failed to produce GM-CSF. In vivo, GM-CSF expression was localized to activated astrocytes and some inflammatory cells in HIV-1 encephalitis, suggesting paracrine activation of microglia through GM-CSF. Our results demonstrate a complex interplay between CSFs, chemokines, and virus in microglial cells and may have bearing on the interpretation of data derived in vivo and in vitro.

AIDS Dementia Complex↗
PubMed2002

Microglia in brain tumors.

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.

Antigen Presentation↗
PubMed2003

Activation of microglia: a neuroinflammatory role for CAP37.

Recent evidence suggests that inflammation and immune function in the central nervous system (CNS) may play a considerable role in the progression of many neurodegenerative diseases. It is known that microglia, the CNS equivalent of peripheral blood monocytes, may be instrumental in causing neurotoxicity. However, the mediator(s) that activates microglia to produce toxic substances that orchestrate cell death has yet to be elucidated. We have identified a novel inflammatory molecule, cationic antimicrobial protein of molecular weight 37 kDa (CAP37), to the brains of patients dying from Alzheimer's disease. CAP37 is known to be a potent activator and regulator of monocyte function in the systemic circulation. We hypothesize that CAP37, a mediator previously shown to recruit and activate monocytes in the systemic circulation, may also play a role in CNS inflammation by modulating microglial function. Here we demonstrate that CAP37 is a chemoattractant for microglia and that CAP37-treated microglia express class II major histocompatibility antigens and produce proinflammatory cytokines and chemokines. We conclude that CAP37 has the ability to activate microglial cells and suggest that it has the potential to serve as a neuroinflammatory molecule.

Animals↗
PubMed2003

Functional characterization of mannose receptor expressed by immunocompetent mouse microglia.

The mannose receptor is a pattern-recognition receptor involved in innate and adaptive immunity. The receptor is mainly expressed by macrophages and, within the brain, by astrocytes and microglia. This study reports for the first time the effects of two classical proinflammatory (interferon-gamma, IFNgamma) and anti-inflammatory (interleukin-4, IL-4) cytokines on the levels of expression and activity of the mannose receptor expressed by mouse microglia, the brain resident macrophages. As observed for macrophages, IFNgamma treatment led to a decrease and IL-4 to an increase of mannose receptor expression. Consequently, the rates of pinocytosis were strongly upregulated by IL-4 and inhibited by IFNgamma. This latter, however, resumed with time and reached again the constitutive rate of pinocytosis. This recovery resulted from an increased pinocytic activity of the few mannose receptor molecules still expressed by IFNgamma-treated microglia. This may suggest a brain-specific regulation of the effects of IFNgamma since such a phenomenon has not been observed in macrophages. Together, these observations demonstrate that cytokine-stimulated immunocompetent microglia express a functional mannose receptor.

Animals↗
PubMed2004

Fibrillar prion peptide (106-126) and scrapie prion protein hamper phagocytosis in microglia.

The inflammatory response in prion diseases is dominated by microglial activation. As macrophages of the central nervous system, the phagocytic capacity of microglia is well recognized, and it is possible that microglia are involved in the removal and processing of amyloid fibrils, thus preventing their harmful effect. We have analyzed the effects of a synthetic peptide of the human prion protein, PrP(106-126), which can form fibrils, and the pathogenic form of prion protein, PrPsc, on phagocytosis in microglia isolated from neonatal rat brain cultures. To some extent, fibrillar PrP(106-126) is internalized and processed. However, both synthetic prion peptide PrP(106-126) in a fibrillar form and pathogenic prion protein PrPsc severely hamper the phagocytic activity as measured by the uptake of beads by microglia. At a concentration that does not induce microglial death, PrP(106-126) reduced the number of beads internalized and altered their cytoplasmic distribution. This effect was not due to decreased binding of beads to the cell surface, nor restricted to specific classes of receptors. Although the PrP(106-126) did not prevent F-actin and Rac1 accumulation at sites of particle engulfment, it appeared to interfere with a later step of the internalization process.

Actins↗
PubMed2001

Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro.

We have previously developed and characterized isolated microglia and astrocyte cultures from rapid (<4 h) brain autopsies of Alzheimer's disease (AD) and nondemented elderly control (ND) patients. In the present study, we evaluate the inflammatory repertoire of AD and ND microglia cultured from white matter (corpus callosum) and gray matter (superior frontal gyrus) with respect to three major proinflammatory cytokines, three chemokines, a classical pathway complement component, a scavenger cell growth factor, and a reactive nitrogen intermediate. Significant, dose-dependent increases in the production of pro-interleukin-1beta (pro-IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide-1alpha (MIP-1alpha), IL-8, and macrophage colony-stimulating factor (M-CSF) were observed after exposure to pre-aggregated amyloid beta peptide (1-42) (Abeta1-42). Across constitutive and Abeta-stimulated conditions, secretion of complement component C1q, a reactive nitrogen intermediate, and M-CSF was significantly higher in AD compared with ND microglia. Taken together with previous in situ hybridization findings, these results demonstrate unequivocally that elderly human microglia provide a brain endogenous source for a wide range of inflammatory mediators.

Aged↗
PubMed2001

Early expression of glutamate transporter proteins in ramified microglia after controlled cortical impact injury in the rat.

Traumatic brain injury is followed by increased extracellular glutamate concentration. Uptake of glutamate is mainly mediated by the glial glutamate transporters GLAST and GLT-1. Extent and distribution of GLAST and GLT-1 were studied in a rat model of controlled cortical impact injury (CCII). Western Blot analysis revealed lowest levels of GLAST and GLT-1 with a decrease by 40%-54% and 42%-49% between 24 and 72 h posttrauma. By 8 h after CCII, CSF glutamate levels were increased (10.5 microM vs. 2.56 microM in controls; P < 0.001), reaching maximum values by 48 h. A significant increase in de novo GLAST and GLT-1 expressing ramified microglia was observed within 4 h, reached a stable level by 48 h, and remained high up to 72 h after CCII. Furthermore, ramified microglia de novo expressed the neuronal glutamate transporter EAAC1 after CCII. Following CCII, GLAST/GLT-1 and GFAP coexpressing astrocytes were immediately reduced, reaching minimum levels within 8 h. This reduction of expression could be either due to protein downregulation or loss of astrocytes. At 72 h, a marked population of GLAST- and GLT-1-positive reactive astrocytes appeared. These results support the hypothesis that reduced astrocytic GLAST and GLT-1 protein levels following CCII contribute to evolving secondary injury. Microglia are capable of de novo expressing glutamate transporter proteins, indicating that the expression of glial and neuronal glutamate transporters is not restricted to a specific glial or neuronal lineage. Ramified microglia may play an important compensatory role in the early regulation of extracellular glutamate after CCII.

ATP-Binding Cassette Transporters↗
PubMed2001

Immune function of microglia.

During the past decade, mechanisms involved in the immune surveillance of the central nervous system (CNS) have moved to the forefront of neuropathological research mainly because of the recognition that most neurological disorders involve activation and, possibly, dysregulation of microglia, the intrinsic macrophages of the CNS. Increasing evidence indicates that, in addition to their well-established phagocytic function, microglia may also participate in the regulation of non specific inflammation as well as adaptive immune responses. This article focuses on the signals regulating microglia innate immune functions, the role of microglia in antigen presentation, and their possible involvement in the development of CNS immunopathology.

Animals↗
PubMed2004

Increased cytotoxic potential of microglia from ALS-transgenic mice.

Amyotrophic lateral sclerosis is a fatal, adult-onset motor neuron disease. A subset of cases is caused by mutations of superoxide dismutase 1 (SOD1) gene. The mechanisms how the mutations in this ubiquitous enzyme mediate the highly selective motor neuron degeneration, however, remain poorly understood. Recent results from transgenic animal models suggest a "non-cell autonomous" mechanism; i.e., cells other than neurons play an active role in motor neuron death. To investigate a possible effect of mtSOD1 on microglial cells, we compared primary cultured microglia from mtSOD1-transgenic mice and nontransgenic litter controls at neonatal (3 days) and adult (60 days) age. We found that mtSOD1 expression increases the production of TNF-alpha and attenuates IL-6-release by LPS-activated adult microglia. Neonatal microglia, however, showed no differences. Our findings suggest an increased cytotoxic potential of adult mtSOD1 microglia, which only becomes apparent after microglial activation.

Age Factors↗