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At least 829 records · Page 46Linked to original sources
PubMed2002

Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: Implications in neurological diseases.

The ability of microglia, the brain's resident macrophage, to present antigen through the class II major histocompatibility complex (MHC) to T cells allows these normally quiescent cells to play a critical role in shaping the outcome of many neurological diseases. The expression of class II MHC antigens and the costimulatory molecules CD40 and B7 on microglia and infiltrating macrophages is regulated through a complex network of cytokines in the inflamed brain. In this review, we describe the molecular mechanisms underlying class II MHC, CD40 and B7 regulation in microglia and macrophages. Our focus is on the cis-elements in the promoters of their genes and the transcription factors activated by cytokines that bind them. The functional implications of aberrant class II MHC, CD40 and B7 expression by microglia and macrophages as related to the diseases of Multiple Sclerosis and Alzheimer's Disease are discussed.

B7-1 Antigen↗
PubMed2004

A novel action of minocycline: inhibition of human immunodeficiency virus type 1 infection in microglia.

Human immunodeficiency virus type 1 (HIV-1) infection of the brain produces a characteristic disease called acquired immunodeficiency syndrome (AIDS) dementia in which productive infection and inflammatory activation of microglia and macrophages play a central role. In this report, the authors demonstrate that minocycline (MC), a second-generation tetracycline with proven safety and penetration to the central nervous system, potently inhibited viral production from microglia. Inhibition of viral release was sustained through the entire course of infection and even when the drug exposure was limited to the first day of infection. Minocycline was effective even at low viral doses, and against R5- and X4R5-HIV, as well as in single-cycle reporter virus assays. Electrophoretic mobility shift analysis showed that minocycline inhibited nuclear factor (NF)-kappaB activation in microglia. HIV-1 long terminal repeat (LTR)-promoter activity in U38 cells was also inhibited. These results, combined with recently demonstrated in vivo anti-inflammatory effects of MC on microglia, suggest a potential utility for MC as an effective adjunct therapy for AIDS dementia.

Cell Culture Techniques↗
PubMed2002

Regulation of CC chemokine receptor 5 and CD4 expression and human immunodeficiency virus type 1 replication in human macrophages and microglia by T helper type 2 cytokines.

Macrophages, microglia, and other mononuclear phagocytes serve as cellular reservoirs for viral persistence in patients with acquired immunodeficiency syndrome. To understand host mechanisms that affect human immunodeficiency virus type 1 (HIV-1) pathogenesis by modulating expression of coreceptors, cytokine regulation of CC chemokine receptor 5 (CCR5) and CD4 expression on monocytes, monocyte-derived macrophages (MDMs), and microglia was investigated. Interleukin (IL)-4 and IL-10 enhanced the entry and replication of HIV-1 in microglia through up-regulation of CD4 and CCR5 expression, respectively. IL-4 stimulated HIV-1 replication in MDMs but down-regulated CD4 and CCR5 expression and inhibited virus entry, whereas IL-10 had the opposite effects. Thus, mechanisms independent of CCR5 and CD4 expression levels are involved in pathways that regulate HIV-1 replication in MDMs. CCR5 up-regulation by IL-10 was associated with increased migration of microglia in response to macrophage inflammatory protein-1beta. These findings suggest that increased production of T helper type 2 cytokines in the later stages of disease can enhance virus entry and replication in mononuclear phagocytes and facilitate chemotactic migration.

CD4 Antigens↗
PubMed2002

Infection of baboon microglia with SIV-HIV recombinant viruses: role of CD4 and chemokine receptors.

Microglia constitute the primary cell type infected with HIV in the brain and play a major role in viral persistence in the CNS and in the development of AIDS dementia. Lack of a suitable animal model and limitations in the availability of human tissues hinder most HIV/AIDS studies investigating the neuropathogenesis of AIDS dementia. The aims of this study were to determine whether baboon microglia can be productively infected with SIV-HIV (SHIV) recombinant viruses in vitro and whether they express HIV-1 receptors and coreceptors. Our results show the presence of mRNA for CD4, CCR5, and CXCR4 chemokine receptors on baboon microglial cells. Microglia lacked mRNA for the CCR3 chemokine receptor. We also show productive infection of baboon microglial cells by two SHIV isolates, SHIV-KU and SHIV-89.6P, and blockade of the infection with soluble CD4 protein, CCR5, and CXCR4 monoclonal antibodies. This study demonstrating the feasibility of infecting baboon microglia with SHIV isolates is an important first step in using the baboon as an alternative nonhuman primate model to study HIV neuropathogenesis.

Animals↗
PubMedDate not supplied

The role of microglia in paraquat-induced dopaminergic neurotoxicity.

The herbicide paraquat (PQ) has been implicated as a potential risk factor for the development of Parkinson's disease. In this study, PQ (0.5-1 microM) was shown to be selectively toxic to dopaminergic (DA) neurons through the activation of microglial NADPH oxidase and the generation of superoxide. Neuron-glia cultures exposed to PQ exhibited a decrease in DA uptake and a decline in the number of tyrosine hydroxylase-immunoreactive cells. The selectivity of PQ for DA neurons was confirmed when PQ failed to alter gamma-aminobutyric acid uptake in neuron-glia cultures. Microglia-depleted cultures exposed to 1 microM PQ failed to demonstrate a reduction in DA uptake, identifying microglia as the critical cell type mediating PQ neurotoxicity. Neuron-glia cultures treated with PQ failed to generate tumor necrosis factor-alpha and nitric oxide. However, microglia-enriched cultures exposed to PQ produced extracellular superoxide, supporting the notion that microglia are a source of PQ-derived oxidative stress. Neuron-glia cultures from NADPH oxidase-deficient (PHOX-/-) mice, which lack the functional catalytic subunit of NADPH oxidase and are unable to produce the respiratory burst, failed to show neurotoxicity in response to PQ, in contrast to PHOX+/+ mice. Here we report a novel mechanism of PQinduced oxidative stress, where at lower doses, the indirect insult generated from microglial NADPH oxidase is the essential factor mediating DA neurotoxicity.

Animals↗
PubMed2000

The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity.

This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.

Adult↗
PubMed2003

Anti-HIV drugs decrease the expression of matrix metalloproteinases in astrocytes and microglia.

The introduction of potent antiretroviral drugs for the treatment of patients with human immunodeficiency virus (HIV) infection has dramatically reduced the prevalence of HIV-associated neurological disorders. Such diseases can be mediated by proteolytic enzymes, i.e. matrix metalloproteinases (MMPs) and, in particular gelatinases, released from glial cells. The aim of this study was to investigate whether the antiretroviral drugs commonly used for the treatment of HIV-infected patients modulate the activity of MMPs in astrocyte and microglial cultures. Primary cultures of rat astrocyte and microglia were treated with different doses of zidovudine (AZT) or indinavir (IDV) for 20 h and simultaneously activated by exposure to lipopolysaccharide (LPS). Culture supernatants collected from astrocytes and microglia after 24 h incubation were subjected to gelatin zymography and western blot analysis for the assessment of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) protein levels. Total RNA was extracted from glial cells and used for reverse transcriptase-polymerase chain reaction for the assessment of mRNA expression. Our results indicate that both astrocyte and microglial cells constitutively express MMP-2 mRNA and protein. LPS treatment increased MMP-2 mRNA and protein expression in astrocytes, but not in microglial cells. The treatment with both AZT and IDV dose-dependently inhibited the expression of MMP-2 in astrocytes, whereas it had no effect on microglial cells. The expression of MMP-9 in both astrocytes and microglia was induced by LPS treatment and was dose-dependently inhibited by AZT and IDV treatment in LPS-stimulated astrocytes and microglia. These results raise the possibility that AZT and IDV interfere directly with MMP production in glial cells and independently from their antiviral activity, thus suggesting the possible therapeutical use in neurological diseases associated with MMPs involvement.

Animals↗
PubMed2004

Microglia in the cerebral wall of the human telencephalon at second trimester.

We have recently begun to gain a clearer understanding of the phasing and patterns of colonization of the developing human brain by microglia. In this study we investigated the distribution, morphology and phenotype of microglia specifically within the wall of the human telencephalon from 12 to 24 gestational weeks (gw), a period that corresponds to the development of thalamocortical fibres passing through the transient subplate region of the developing cerebral wall. Sections from a total of 45 human fetal brains were immunoreacted to detect CD68 and MHC class II antigens and histochemically reacted with RCA-1 and tomato lectins. These markers were differentially expressed by anatomically discrete populations of microglia in the cerebral wall: two cell populations were noted during the initial phase of colonization (12-14 gw): (i) CD68++ RCA-1+ MHC II- amoeboid cells aligned within the subplate, and (ii) RCA-1++ CD68- MHC II- progenitors in the marginal layer and lower cortical plate that progressively ramified within the subplate, without seemingly passing through an 'amoeboid' state. At this stage microglia were largely absent from the germinal layers and the intermediate zone. From 14 to 15 gw, however, MHC class II positive cells were also detected within germinal layers and in the corpus callosum, and these cells, which coexpressed CD68 antigen (a marker associated with phagocytosis), further populated the lower half of the telencephalon from 18 to 24 gw. These findings are discussed in relation to developmental events that take place during the second trimester within the wall of the telencephalon.

Antigens, CD↗
PubMed2000

Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics.

Glia play a major role in neuronal migration, synapse formation, and control of neurotransmission in the developing and mature nervous system. This study investigated whether chronic schizophrenia is associated with glial changes in 3 regions of the cerebral cortex: dorsolateral prefrontal cortex (Brodmann's area 9), the superior temporal gyrus (area 22), and the anterior cingulate gyrus (area 24). In a blind study, astroglia and microglia were identified immunocytochemically in frozen sections from postmortem schizophrenic and control brains. Astroglia and microglia were identified using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR) respectively. They were then quantified for each cortical layer. Significant differences were found in HLA-DR+ microglial numerical density in 2 of the areas. A 28% increase (p < 0.05) was found in area 9 in 8 schizophrenics (115 +/- 9 cells/mm2) compared with 10 controls (89 +/- 5 cells/mm2), when combining all cortical layers and both cerebral hemispheres. For area 22, there was a 57% increase (p < 0.01) in microglia in 7 schizophrenics (139 +/- 6 cells/mm2) compared with 10 controls (88 +/- 5 cells/mm2). In area 24 the same trend was evident, but the results did not reach significance. Microglial number was further analyzed for each cortical layer, which confirmed the overall pattern. For all areas, numerical density of astroglia showed no significant differences between schizophrenics and controls. Cortical thickness was measured in all areas and total neuronal numerical density was estimated for area 22. Again, no significant differences were found between schizophrenics and controls. This study demonstrates a specific increase in the numerical density of HLA-DR+ microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, which might be implicated in possible changes in cortical neuropil architecture in schizophrenia.

Age Factors↗
PubMed2000

Phosphatidylserine-dependent phagocytosis of apoptotic glioma cells by normal human microglia, astrocytes, and glioma cells.

Apoptotic cells display signals that trigger phagocytic removal by macrophages or neighboring cells. To better understand the signals triggering phagocytosis of apoptotic glioma cells, and to identify the cells that might be involved in the phagocytic process, U-251 MG glioma cells were made apoptotic by etoposide (25 microg/ml) treatment and were incubated with normal human astrocytes (NHA), glioma cells, or microglia. Extent of phagocytosis was assessed by an in vitro phagocytosis assay. After 3 h of incubation with apoptotic cells, phagocytes tested were washed to remove nonengulfed cells, then fixed, stained, and counted to determine phagocytosis index (PI). NHA, glioma cells, and microglia all phagocytosed apoptotic, but not nonapoptotic, glioma cells. Microglia, however, had a PI approximately 4-fold higher than did either NHA or glioma cells. Binding of phosphatidylserine (PS) on apoptotic glioma cell membranes by annexin-V inhibited phagocytosis by 90% in both microglia and NHA. The activity of an enzyme (scramblase) that moves PS from the inner cell membrane to the outer cell membrane was also increased in apoptotic glioma cells. These results suggest that a variety of cells present in and near gliomas in vivo can remove glioma cells in a PS-dependent scramblase-mediated fashion. Manipulation of scramblase and/or PS exposure in glioma cells may therefore be a means of triggering phagocytic removal of glioma cells.

Apoptosis↗
PubMed2004

Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism.

Recent evidence suggests that the mechanism of manganese (Mn) neurotoxicity involves activation of microglia and/or astrocytes; as a consequence, neurons adjacent to the activated microglia may be injured. Mn modulation of proinflammatory cytokine expression by microglia has not been investigated. Therefore, the objectives of this research were to (1) assess whether Mn induces proinflammatory cytokine expression and/or modulates lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines and (2) investigate possible mechanisms for such an induction. N9 microglia were exposed in vitro to increasing concentrations (50-1000 microM) of Mn in the presence or absence of LPS (10, 100, or 500 ng/ml). After various incubation times (up to 48 h), media levels of several cytokines and nitric oxide (NO) were determined, as was the expression of the inducible form of NO synthase (iNOS). Lactate dehydrogenase (LDH) release into the medium and the cellular uptake of Neutral Red were used as general measures for cytotoxicity. In the absence of LPS, Mn moderately increased interleukin-6 and tumor necrosis factor alpha (TNF-a) production only at higher Mn concentrations, which were cytotoxic. At all LPS doses, however, proinflammatory cytokine production was dose-dependently increased by Mn. Similarly, LPS-induced NO production and iNOS expression were substantially enhanced by Mn. Pharmacological manipulations indicated that nuclear factor kappa B (NFkappaB) activation is critical for the observed enhancement of cytokine and NO production. Within the context of inflammation, increased production of proinflammatory cytokines and NO by Mn could be an important part of the mechanism by which Mn exerts its neurotoxicity.

Acetylcysteine↗
PubMed2005

Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease.

A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of alpha-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human alpha-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated alpha-synuclein. Furthermore, microglial enhancement of alpha-synuclein-mediated neurotoxicity depended on phagocytosis of alpha-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of etiology, may release aggregated alpha-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in alpha-synuclein-mediated microglial activation and associated neurotoxicity.

Animals↗
PubMed2006

Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by beta-amyloid.

Brain inflammation is characterized by a reactive gliosis involving the activation of astrocytes and microglia. This process, common to many brain injuries and diseases, underlies important phenotypic changes in these two glial cell types. One characteristic feature of astrocytes is their high level of intercellular communication mediated by gap junctions. Previously, we have reported that astrocyte gap junctional communication (AGJC) and the expression of connexin 43 (Cx43), the main constitutive protein of gap junctions, are inhibited in microglia (MG)-astrocyte cocultures. Here, we report that bacterial lipopolysaccharide activation of microglia increases their inhibitory effect on Cx43 expression and AGJC. This inhibition is mimicked by treating astrocyte cultures with conditioned medium harvested from activated microglia. Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were identified as being the main factors responsible for this conditioned medium-mediated activity. Interestingly, an inflammatory response characterized by MG activation and reactive astrocytes occurs in Alzheimer's disease, at sites of beta-amyloid (Abeta) deposits. We found that this peptide potentiates the inhibitory effect of a conditioned medium diluted at a concentration that is not effective per se. This potentiation is prevented by treating astrocytes with specific blockers of IL-1beta and TNF-alpha activities. Thus, the suppression of communication between astrocytes, induced by activated MG could contribute to the proposed role of reactive gliosis in this neurodegenerative disease.

Amyloid beta-Peptides↗
PubMed2005

Gene expression profile of activated microglia under conditions associated with dopamine neuronal damage.

Microglia are the resident antigen-presenting cells within the central nervous system (CNS), and they serve immune-like functions in protecting the brain against injury and invading pathogens. By contrast, activated microglia can secrete numerous reactants that damage neurons. The pathogenesis of various neurodegenerative diseases has been associated with microglial activation, but the signaling pathways that program a neuronally protective or destructive phenotype in microglia are not known. To increase the understanding of microglial activation, microarray analysis was used to profile the transcriptome of BV-2 microglial cells after activation. Microglia were activated by lipopolysaccharide, the HIV neurotoxic protein TAT, and dopamine quinone, each of which has been linked to dopamine neuronal damage. We identified 210 of 9882 genes whose expression was differentially regulated by all activators (116 increased and 94 decreased in expression). Gene ontology analysis assigned up-regulated genes to a number of specific biological processes and molecular functions, including immune response, inflammation, and cytokine/chemokine activity. Genes down-regulated in expression contribute to conditions that are permissive of microglial migration, lowered adhesion to matrix, lessened phagocytosis, and reduction in receptors that oppose chemotaxis and inflammation. These results elaborate a broad profile of microglial genes whose expression is altered by conditions associated with both neurodegenerative diseases and microglial activation.

Animals↗
PubMed1997

Activated human microglia produce the excitotoxin quinolinic acid.

We aimed to determine the relative role of quinolinic acid synthesis in purified human microglia, monocyte-derived macrophages and astrocytes in the human brain following immune stimulation. Microglia and macrophages significantly increased quinolinic acid synthesis from tryptophan following activation by either lipopolysaccharide or interferon-gamma. Quinolinic acid synthesis by individual microglia was heterogeneous, and its production by activated macrophages was approximately 32-fold greater than its microglial synthesis. Quinolinic acid synthesis by astrocytes was undetectable. Microglia may, therefore, be the primary endogenous cell type responsible for quinolinic acid synthesis in the brain parenchyma. However, under pathological conditions which precipitate blood-brain barrier compromise and/or leukocytic infiltration, intracerebral quinolinic acid may be derived chiefly from cells of the peripheral immune system such as activated macrophages.

Brain↗
PubMed1998

Activated microglia cause iron-dependent lipid peroxidation in the presence of ferritin.

Ferritin contains most of the iron found in the brain, and the release of iron from ferritin has an essential role in iron-dependent lipid peroxidation. We examined the effect of cultured microglia on the ferritin-dependent lipid peroxidation of phospholipid liposomes monitored by the formation of thiobarbituric acid-reactive substances. Microglia stimulated by phorbol myristate acetate caused lipid peroxidation in the presence of ferritin. This lipid peroxidation was mediated by superoxide produced by the microglia and iron released from the ferritin. Lipid peroxidation induced by activated microglia may be partly responsible for the oxidative damage that is thought to occur in Parkinson's disease and other neurodegenerative disorders.

Animals↗
PubMed2004

Insulin-like growth factor binding protein-1-6 expression in activated microglia.

In the CNS insulin-like growth factor-1 (IGF-1) enhances survival of neurons, promotes myelin synthesis and acts as a mitogen for microglia. The effects of IGF-1 are regulated by a family of 6 IGF binding proteins (IGFBPs). We investigated mRNA expression patterns of IGFBPs in primary rat microglia under basal conditions and after activation with lipopolysaccharide (LPS). Under basal conditions, microglia expressed IGFBP-2 to -6, whereas, IGFBP-1 could not be detected. Following 2 h treatment with LPS mRNA levels for IGFBP-4 and -6 displayed a down regulation, and IGFBP-5 became undetectable. Levels of IGFBP-2 and -3 remained unaltered. Expression patterns of IGFBPs might play an important role in regulating the autocrine/paracrine IGF-1 actions on microglia under inflammatory conditions.

Animals↗
PubMedDate not supplied

Activation mechanism of brain microglia in patients with diffuse neurofibrillary tangles with calcification: a comparison with Alzheimer disease.

Diffuse neurofibrillary tangles with calcification (DNTC) is an atypical dementia and is characterized pathologically by diffuse neurofibrillary tangles (NFTs) without senile plaques (SPs). In this study, we investigated the distribution of human leukocyte antigen (HLA)-DR-positive activated microglia in postmortem brain tissue of six patients with DNTC and six patients with Alzheimer disease (AD). HLA-DR-positive activated microglia were observed to associate with SPs in AD. In the DNTC brain, which lacks SPs, HLA-DR-positive microglia were mainly accumulated around weakly tau-positive NFTs, which were also positive for anti-amyloid-P and anti-C3d antibodies. The results of this study suggest that the complement pathway is also activated in the DNTC brain and that immune and inflammatory responses, including microglia activation, may occur around extracellular NFTs in DNTC patients.

Aged↗