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PubMed1995

Chemotaxis and accumulation of nerve growth factor by microglia and macrophages.

Astrocytes and microglia play a critical role in the reaction of the central nervous system (CNS) to trauma. Although both astrocytes and microglia can produce it, accumulation of immunoreactive nerve growth factor (the prototype neurotrophin important for the survival of several classes of neurons) was observed selectively in cultured microglia and macrophages, rather than in astrocytes. Furthermore, microglia were found to display chemotaxis toward a localized source of nerve growth factor and, as demonstrated by autoradiography, take up extracellular nerve growth factor. These findings suggest that microglia, the brain's own macrophages, participate in the regulation of nerve growth factor availability in a site-specific manner. This novel function may assume a general importance both in the CNS and the peripheral nervous system at critical times after trauma when this neurotrophin is needed for nerve cell survival.

Animals↗
PubMed1998

Morphine enhances complement receptor-mediated phagocytosis of Cryptococcus neoformans by human microglia.

Recent studies have shown that opiates modulate the function of microglia, the resident macrophages of the brain. In this study, the effect of morphine on phagocytosis by human fetal microglial cells of the opportunistic fungus Cryptococcus neoformans was studied. Contrary to earlier findings with swine microglia, opsonization was required for the phagocytosis of C. neoformans by human microglia. Moreover, morphine (10(-8)M) was shown to augment uptake of opsonized C. neoformans by over 50%. This contrasts with the earlier finding of morphine-induced inhibition of phagocytosis of nonopsonized cryptococci by swine microglia. The effect of morphine on cryptococcal phagocytosis by human microglia was reversed by treatment of microglial cells with mu opiate receptor antagonists as well as by addition of anti-complement receptor antibodies to the cell cultures, indicating that both the mu opiate receptor and the complement receptor are involved in morphine-enhanced phagocytosis. These findings support the concept of opiates as neuroimmunomodulatory agents and demonstrate that the effects of opiates on microglial cells may be influenced by the animal species from which the cells are derived.

Analgesics, Opioid↗
PubMed2001

Microglia, astrocytes, and macrophages react differentially to central and peripheral lesions in the developing and mature rat whisker-to-barrel pathway: a study using immunohistochemistry for lipocortin1, phosphotyrosine, s100 beta, and mannose receptors.

Adult and neonatal rats were subjected to transection of the left infraorbital nerve or ablation of the left parietal cortex. The ensuing glial reaction in the whisker-to-barrel pathway was studied with immunohistochemistry for Lipocortin1- (LC1+), phosphotyrosine- (PY+), S100 beta- (S100 beta+), and mannose receptor- (MR+) immunoreactive microglia, astrocytes, and macrophages. Four days after infraorbital nerve transection in adult rats, LC1+ and PY+ microglia were prominently increased in the trigeminal sensory brain-stem nuclei on the deafferented side compared with the intact side. Changes were negligible at the second synapse of the pathway, i.e., the thalamic ventroposterior medial nucleus. Cortical ablation in adults led to an increase in microglia in the ipsilateral ventroposterior medial nucleus that reciprocally connects with the ablated cortex. Moreover, microglial reactions occurred in the contralateral trigeminal sensory brain-stem nuclei in which corticofugal projections from the ablated cortex terminate. S100 beta+ astrocytes, in contrast, appeared unaltered after both types of lesion in adults. In neonates, LC1+, PY+, and S100 beta+ cells did not have the adult morphology of microglia or astrocytes. Four days after nerve transection, LC1+ and PY+ cells were sparse and remained unchanged. In contrast, S100 beta+ cells substantially increased in the deafferented trigeminal brain-stem nuclei. Four days after cortical ablation in neonates, LC1+, PY+, and S100 beta+ cells had accumulated in the deprived thalamus. In contrast to adults, many of these cells were MR+ macrophages. In the deprived brain-stem, only S100 beta+ cells increased and none were macrophages. Therefore, macrophages do not appear to stem from microglia, and neonatal LC1+, PY+, and S100 beta+ cells may possess functions different from those in adults.

Aging↗
PubMed1998

Microglia in cell culture and in transplantation therapy for central nervous system disease.

The central nervous system (CNS) is host to a significant population of macrophage-like cells known as microglia. In addition to these cells which reside within the parenchyma, a diverse array of macrophages are present in meningeal, perivascular, and other peripheral locations. The role that microglia and other CNS macrophages play in disease and injury is under intensive investigation, and functions in development and in the normal adult are just beginning to be explored. At present the biology of these cells represents one of the most fertile areas of CNS research. This article describes methodology for the isolation and maintenance of microglia in cell cultures prepared from murine and feline animals. Various approaches to identify microglia are provided, using antibody, lectin, or scavenger receptor ligand. Assays to confirm macrophage-like functional activity, including phagocytosis, lysosomal enzyme activity, and motility, are described. Findings regarding the origin and development of microglia and results of transplantation studies are reviewed. Based on these data, a strategy is presented that proposes to use the microglial cell lineage to effectively deliver therapeutic compounds to the CNS from the peripheral circulation.

Animals↗
PubMed1996

The effect of simian immunodeficiency virus infection in vitro and in vivo on the cytokine production of isolated microglia and peripheral macrophages from rhesus monkey.

Microglia are the major target for human immunodeficiency virus (HIV) infection within the central nervous system. Because only a few cells are productively infected, it has been suggested that an aberrant cytokine production by this cell population may be an indirect mechanism leading to the development of neurological disorders in HIV-infected patients. Therefore we decided to study the secretion pattern of several interleukins (IL) by microglial cells and peripheral blood macrophages isolated from uninfected and simian immunodeficiency virus (SIV)-infected Rhesus monkeys. We found that uninfected, unstimulated primate microglia produce more IL-6 and less TNF alpha than peripheral blood macrophages, but generate comparable levels of IL-1 beta and IL-8. After infection with SIV in vitro, synthesis of all cytokines tested is increased compared to uninfected cultures and to peripheral blood macrophages. Microglia isolated from infected animals produce more IL-8 and TNF alpha than the uninfected cultures and display a strongly increased capacity to secrete TNF alpha upon stimulation with lipopolysaccharide. In addition, production of IL-6 by in vivo-infected microglia increases with time in culture to very high levels despite the fact that only a few cells contained replicating virus. These findings clearly show that the cytokine production of microglia is impaired after SIV infection both in vitro and in vivo and that a low level of viral replication is sufficient for these alterations to occur. In conclusion, the results of this study further support a possible role of cytokines in the pathogenesis of neuro-AIDS.

Animals↗
PubMed2000

In vivo infection of ramified microglia from adult cat central nervous system by feline immunodeficiency virus.

Infection of microglial cells by the human immunodeficiency virus (HIV) is supposed to play an important role in the pathogenesis of AIDS-related central nervous system (CNS) complications. So far, however, experimental data about interactions between HIV and ramified microglia from the adult CNS were only occasionally reported, making it difficult to understand the exact nature of pathogenic events contributing to HIV-encephalopathy. Therefore, we used the animal model of feline immunodeficiency virus (FIV) infection of domestic cats to establish an experimental system which is suitable for studying the relationships between an immunodeficiency virus and the mature ramified microglia of the central nervous system. By means of density gradient centrifugation approximately 95% pure microglial cells could be isolated from adult feline brain that were characterized by their CD45(low) phenotype. Resident microglia extracted from the CNS of experimentally infected cats harbored FIV-specific DNA and cocultivation with mitogen-activated, but uninfected peripheral blood mononuclear cells (PBMC) resulted in recovery of high-titered infectious virus. Double labeling of brain cell monocultures explanted from persistently infected animals for both microglia and FIV markers disclosed less than 1% of viral antigen expressing microglial cells. This suggests that during the subclinical phase of the infection only a small number of brain-resident macrophages are productively infected. However, interaction of FIV-infected microglia and inflammatory lymphocytes may promote viral replication, thus supporting viral spread in brain tissue.

Animals↗
PubMed1998

Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain.

Microglia-mediated inflammatory responses have been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. The strong age association of Alzheimer's disease incidence suggests that events in normal aging may promote such responses. We used immunohistochemistry and computerized image analysis to determine the numbers, size, activation state, and immunoreactive intensity of interleukin-1 alpha-immunoreactive (IL-1 alpha +) microglia in mesial temporal lobe of 20 neurologically normal individuals, 2-80 years of age. We also used Northern analysis to determine tissue levels of IL-1 alpha mRNA in an additional 11 neurologically normal individuals aged 1 day to 78 years. IL-1 alpha + microglia were characterized as primed, enlarged, or phagocytic (enlarged with heterogeneous cytoplasmic contents) based on morphology. These three microglial subtypes showed significant differences in size [27 +/- 1 58 +/- 2 114 +/- 6 (mean +/- SEM) micron 2/cell, respectively, P < 0.001 for each comparison] and in immunoreactive intensity [60 +/- 1 68 +/- 2 79 +/- 2 (arbitrary units), respectively, P < 0.001 or better for each comparison]. There were significant age-associated increases in the total numbers of activated IL-1 alpha + microglia. Among microglial subtypes, there were significant increases in the numbers of enlarged (threefold) and especially phagocytic (elevenfold), but not primed, microglia. Tissue IL-1 alpha mRNA levels were higher in individuals over 60 than in those less than 60 (P < 0.05). The age-associated increases in microglial activation were independent of postmortem interval, patient sex, and the presence of Alzheimer-type 'senile' changes. Age-associated increases in microglial activation and IL-1 expression may contribute to the age-associated increased risk of Alzheimer's disease.

Adolescent↗
PubMed2005

Protein 4.1 G localizes in rodent microglia.

Although it was reported that protein 4.1 G, a cytoskeletal protein characterized by its general expression in the body, interacts with some signal transduction molecules in the central nervous system (CNS), its distribution and significance in vivo remained to be elucidated. In the present study, we have identified 4.1 G-positive cells in the rodent CNS, and demonstrated its immunolocalization in the developing mouse CNS. In the rodent CNS, 4.1 G was colocalized with markers for microglia, such as CD45, OX-42 and ionized calcium-binding adapter molecule 1 (Iba1), but not with markers for neuronal or other glial cells. Additionally, colocalization of 4.1 G and A1 adenosine receptor was observed in the mouse cerebrum. In a mixed glial culture, most OX-42-positive microglia were positive for 4.1 G, and 4.1 G isoforms of the same molecular weight as in the rat brain were expressed in cultured microglia, where 4.1 G mRNA was detected by RT-PCR. In the developing mouse cerebral cortex, 4.1 G was detected in immature microglia, which were positive for Iba1. These results indicate that 4.1 G in the CNS is mainly distributed in microglia in vivo. Considering the interactions between 4.1 G and the signal transduction molecules, putative roles have been proposed for 4.1 G in microglial functions in the CNS.

Animals↗
PubMed1994

Early response of brain resident microglia to kainic acid-induced hippocampal lesions.

We investigated the early response of microglia with complement and other proteins in well controlled rat central nervous system lesions. A selective neuronal degeneration in the hippocampal CA3 region was induced without direct tissue damage by an intraventricular injection of a small amount of kainic acid. As early as 1 h post injection, complement proteins C1q, C4, and C3 and immunoglobulin(Ig)G were found in the lesioned area. After 2 h, non-specific leakage of other plasma proteins occurred. By 3 h, reactive microglia gathered around the injured pyramidal neurons. Areas surrounding the lesions were depleted, on the other hand, indicating that these reactive microglia had originally resided in and migrated from such vacant areas. Upregulation of ICAM-1 expression by vascular endothelial cells commenced after 6 h. LFA-1-positive leucocytes were, then, accumulated in the vasculature, which was followed by an infiltration of leucocytes into the lesioned brain parenchyma. These results indicate that, following an acute neuronal injury, the response of the humoral factors such as complement proteins and IgG precedes the microglial reaction. Activation of vascular endothelial cells and subsequent infiltration of blood leucocytes occurs much later than the activation and migration of brain resident microglia. The origin of complement proteins and IgG in the lesioned brain parenchyma remains to be determined, although the production of complement proteins by microglia is suggested.

Animals↗
PubMed1994

Rat brain microglia and peritoneal macrophages show similar responses to respiratory burst stimulants.

Respiratory burst activity was compared between cultured newborn rat microglia and directly harvested adult rat peritoneal macrophages using a Clarke oxygen electrode system. Both types of cells showed stimulated oxygen consumption almost immediately after the administration of opsonized zymosan, phorbol myristate acetate, concanavalin A, or tuftsin. The absolute values of stimulated oxygen consumption after administration of these agents ranged from 0.11 to 0.99 nmol per min per million cells, with some variation in relative response of microglia compared with peritoneal macrophages. After lysis of cells with deoxycholate, or disruption by sonication, oxygen consumption was restored by NADPH for stimulated microglia but not stimulated astrocytes. The potential for stimulated microglia to generate oxygen free radicals may have implications in several degenerative neurological diseases where activated microglia are found in association with the lesions.

Animals↗
PubMed1995

Human microglia mediate anti-Cryptococcus neoformans activity in the presence of specific antibody.

The interaction of the opportunistic fungus Cryptococcus neoformans with human microglia was studied in vitro in the presence and absence of capsule binding antibody. In the absence of capsule binding antibody there was little or no phagocytosis. Addition of the murine monoclonal antibody (mAb) 2H1 (IgG1, kappa) to the capsular glucuronoxylomannan (GXM) produced a dose-dependent enhancement of C. neoformans phagocytosis by microglia. Phagocytosis resulted in marked inhibition of fungal proliferation. Microglial antifungal activity was studied by colony forming unit assay, L-[3H]leucine incorporation assay, and phase contrast microscopy. At microglia: C. neoformans ratios of 10:1 to 80:1 fungal growth was reduced by 61-95%. Inhibitors of nitric oxide synthase and reactive oxygen intermediates did not prevent antifungal activity mediated by human microglia. Transmission electron microscopic studies revealed that although some internalized yeast cells were killed, the majority were intact consistent with fungistasis. Human microglia cells are potent effector cells against C. neoformans in vitro in the presence of specific antibody. Enhancement of microglial activity in vivo by opsonins may be a useful therapeutic strategy.

Antibodies, Fungal↗
PubMed1995

Release of myelin basic protein-degrading proteolytic activity from microglia and macrophages after infection with Theiler's murine encephalomyelitis virus: comparison between susceptible and resistant mice.

Theiler's murine encephalomyelitis virus (TMEV) produces a chronic inflammatory demyelinating disease in its natural host, the mouse. A delayed-type hypersensitivity (DTH) response to viral antigens generally correlates with susceptibility to the disease and is thought to play an important role in the pathogenesis of demyelination in this model of human multiple sclerosis (MS). The hallmark of DTH responses is the recruitment by activated Th-1 cells of lymphoid cells and especially macrophages in infected areas. It is believed that soluble factors released by these cells would produce tissue damage, particularly myelin breakdown. In the present study, we compared TMEV-infected macrophages and microglia, isolated from both susceptible SJL/J and resistant C57BL/6 mice, for their ability to secrete proteolytic enzymes capable of degrading myelin basic protein. In addition, we studied whether supernatants from infected microglia/macrophages were also capable of killing oligodendrocytes in the same in vitro system. As detected by SDS-PAGE, MBP-degrading proteolytic activity was found only in supernatants from infected SJL/J microglia and macrophages, but not in supernatants collected from infected C57BL/6 microglia and macrophages, or in supernatants from mock-infected SJL/J and C57BL/6 cells. Similarly, incubation of E20.1 cells, an immortalized line of oligodendrocytes, with infected SJL/J, but not C57BL/6 supernatants, resulted in cytotoxic activity. When cells from resistant C57BL/6 mice were treated with LPS, they became susceptible to infection and also secreted proteolytic enzymes. The proteolytic activity released from infected microglia and macrophages was found to be dose-dependent, was inactivated by heat, and was inhibited by phenylmethylsulphonyl fluoride (PMSF). These results indicate that a serine protease is released from infected microglia and macrophages and suggest a role for proteases in TMEV-induced myelin injury.

Animals↗
PubMed1994

Phagocytic microglia release cytokines and cytotoxins that regulate the survival of astrocytes and neurons in culture.

Numerous studies have now shown that microglia secrete factors which may influence the growth and survival of cells in the CNS. We employed glia-neuron co-cultures to investigate the net effect of soluble products from secretory microglia upon astroglia and neurons following microglial activation by a phagocytic signal. Stimulation of microglia produced soluble factors that both increase the number of astroglia and decrease the number of neurons. The astroglial proliferating activity was blocked when incubated with an interleukin-1 (IL-1) receptor antagonist while the neurotoxic effect was inhibited by a N-methyl-D-aspartate (NMDA) receptor antagonist. Recombinant IL-1 served as a potent mitogen for cultured astroglia and promoted neuron survival by indirect actions upon astrocytes. These observations suggest that reactive microglia mediate both astrogliosis and neuronal injury through the simultaneous release of cell growth factors and poisons. The net effect of secretion products from phagocytic microglia is to diminish neuronal survival.

Animals↗
PubMed1995

Mitogenic effects of interleukin-5 on microglia.

Interleukin-3 (IL-3), interleukin-5 (IL-5), and granulocyte macrophage-colony stimulating factor (GM-CSF) are cytokines that bind to receptor complexes comprised of unique alpha-receptor subunits specific for each ligand and a commonly shared beta-receptor subunit. Previous studies have shown that IL-3 and GM-CSF induce mitosis in microglia and macrophage cells, indicating the functional presence of their cognate receptors. In this study, it is shown that the third member of this cytokine group, IL-5, also serves as a microglia mitogen. Proliferative effects were seen in culture on both murine microglia and a murine macrophage cell line, RAW 264.7. Since IL-5 is known to be secreted by both microglia and astrocytes in response to inflammatory stimuli, these results indicate that IL-5 may be involved in the cytokine-immune cascades leading to microglia proliferation in areas affected by disease and tissue damage.

Animals↗
PubMed2003

Plasminogen-induced IL-1beta and TNF-alpha production in microglia is regulated by reactive oxygen species.

Microglia, major immune effector cells in the central nervous system, become activated during brain injury. In this study we showed that the blood component plasminogen/plasmin activates microglia. Plasminogen-induced IL-1beta, TNF-alpha, and iNOS mRNA expression in primary cultured rat microglia and BV2 murine microglial cells. Plasmin caused a similar response. Serine protease inhibitors suppressed both plasminogen- and plasmin-induced IL-1beta and TNF-alpha expression, indicating the importance of serine protease activity in plasminogen/plasmin activation of microglia. Reactive oxygen species (ROS) appeared to play an important role in plasminogen-induced microglial activation, with ROS being generated within 15min of plasminogen treatment, and antioxidants (100 microM trolox and 10mM NAC) reducing IL-1beta and TNF-alpha expression in plasminogen-treated cells. Furthermore, plasminogen stimulated CREB and NF-kappaB DNA binding activity, and this activation was also reduced by trolox and NAC. These results suggest that plasminogen activates microglia via stimulation of ROS production.

Animals↗
PubMed2006

Cell cycle-dependent regulation of kainate-induced inward currents in microglia.

Microglia are reported to have alpha-amino-hydroxy-5-methyl-isoxazole-4-propionate/kainate (KA) types. However, only small population of primary cultured rat microglia (approximately 20%) responded to KA. In the present study, we have attempted to elucidate the regulatory mechanism of responsiveness to KA in GMIR1 rat microglial cell line. When the GMIR1 cells were plated at a low density in the presence of granulocyte macrophage colony-stimulating factor, the proliferation rate increased and reached the peak after 2 days in culture and then gradually decreased because of density-dependent inhibition. At cell proliferation stage, approximately 80% of the GMIR1 cells exhibited glutamate (Glu)- and KA-induced inward currents at cell proliferation stage, whereas only 22.5% of the cells showed responsiveness to Glu and KA at cell quiescent stage. Furthermore, the mean amplitudes of inward currents induced by Glu and KA at cell proliferation stage (13.8+/-3.0 and 8.4+/-0.6 pA) were significantly larger than those obtained at cell quiescent stage (4.7+/-0.8 and 6.2+/-1.2 pA). In the GMIR1 cells, KA-induced inward currents were markedly inhibited by (RS)-3-(2-carboxybenzyl) willardiine (UBP296), a selective antagonist for KA receptors. The KA-responsive cells also responded to (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a selective agonist for GluR5, in both GMIR1 cells and primary cultured rat microglia. Furthermore, mRNA levels of the KA receptor subunits, GluR5 and GluR6, at the cell proliferation stage were significantly higher than those at the cell quiescent stage. Furthermore, the immunoreactivity for GluR6/7 was found to increase in activated microglia in the post-ischemic hippocampus. These results strongly suggest that microglia have functional KA receptors mainly consisting of GluR5 and GluR6, and the expression levels of these subunits are closely regulated by the cell cycle mechanism.

Animals↗
PubMed2004

Inhibition of inducible nitric oxide synthase expression by baicalein in endotoxin/cytokine-stimulated microglia.

Excessive production of nitric oxide (NO) in the central nervous system (CNS) mediated by activation of microglia has been implicated in neurotoxicity after stresses such as ischemia. Baicalein, a polyphenolic flavonoid antioxidant, is known to have anti-inflammatory, anticarcinogenic, and neuroprotective effects. In the present study, we report the inhibitory effect of baicalein on endotoxin/cytokine-induced NO production and inducible nitric oxide synthase (iNOS) gene expression in microglia. Baicalein abolished the endotoxin/cytokine-induced expression of iNOS protein, iNOS mRNA, and iNOS promoter activity in a parallel concentration-dependent manner. The suppression of iNOS expression was not mediated through the down-regulation of tumor necrosis factor-alpha (TNF-alpha) by baicalein because TNF-alpha failed to enhance endotoxin/cytokine-induced NO production in microglia. From the electrophoretic mobility shift assay (EMSA), we found that baicalein exerted a distinct inhibitory effect on the DNA binding activity of transcription factors, and this was significantly greater in nuclear factor IL-6 (NF-IL6) than in nuclear factor kappa B (NF-kappaB) and activated protein 1 (AP-1). Although extracellular signal-regulated kinase (ERK) is critical to iNOS expression, endotoxin/cytokine-stimulated phosphorylation of ERK1/2 was not significantly inhibited by baicalein. These results indicate that NF-IL6 inactivation could be the major determinant for the suppression of NO production by baicalein in microglia. Furthermore, it suggests that the inhibitory effect of baicalein on microglia activation and neurotoxic factor production is responsible for its neuroprotective action.

Animals↗
PubMed2006

Nonparticipation of nuclear factor kappa B (NFkappaB) in the signaling cascade of c-Jun N-terminal kinase (JNK)- and p38 mitogen-activated protein kinase (p38MAPK)-dependent tumor necrosis factor alpha (TNFalpha) induction in lipopolysaccharide (LPS)-stimulated microglia.

The molecular mechanism of cytotoxic cytokine tumor necrosis factor alpha (TNFalpha) induction in microglia remains to be clarified. We have previously reported that p38 mitogen-activated protein kinase (p38MAPK) is an important signaling molecule for the induction of TNFalpha in lipopolysaccharide (LPS)-stimulated microglia. Recently, we have shown that c-Jun N-terminal kinase (JNK) is associated with the induction of TNFalpha. Furthermore, using an NFkappaB inhibitor (SN50), we discovered that activation of nuclear factor kappaB (NFkappaB) may also be linked to TNFalpha induction. We therefore examined the relationship between NFkappaB and the two MAPKs (p38MAPK and JNK) in the signaling cascade of TNFalpha induction in LPS-stimulated microglia. NFkappaB inhibitor SN50 decreased the induction of TNFalpha under the suppressed NFkappaB activation. However, SN50 was found to prevent the activation of MKK3/6-p38MAPK and MKK4-JNK pathways. On the other hand, the other NFkappaB inhibitor ammonium pyrrolidine dithiocarbamate (APDC) neither prevented the activation of p38MAPK and JNK nor inhibited TNFalpha induction in LPS-stimulated microglia, although it was confirmed to serve as an NFkappaB inhibitor. These results suggest that both MKK3/6-p38MAPK and MKK4-JNK pathways are important signaling cascades leading to the induction of TNFalpha in LPS-stimulated microglia, but that NFkappaB itself is not required for this induction.

Animals↗