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At least 433 records · Page 24Linked to original sources
PubMed1994

The effects of subcutaneous injections of glucocorticoids on amoeboid microglia in postnatal rats.

Subcutaneous injections of glucocorticoids into postnatal rats resulted in a drastic reduction in the number of amoeboid microglial cells in the corpus callosum as shown by their labelling with the monoclonal antibodies of the OX-series, ED1, lectin and rhodamine isothiocynate (RhIc). In rats receiving 2 or 3 injections of glucocorticoids and killed at the age of 4 or 7 days, between 40 to 60% of the callosal amoeboid microglial cells were depleted when compared with the corresponding control animals. The cells that survived the glucocorticoid treatments became ramified, while those in the controls of the same age group remained round or amoeboidic. In rats killed at 2 or 3 weeks of age, the microglia became extremely ramified with a concomitant diminution in their immunostaining, particularly in the glucocorticoid-injected rats. In rats receiving glucocorticoid injections along with RhIc, the RhIc-laden amoeboid microglia appeared round and amoeboidic and were intensely stained with OX-42, suggesting their activation and upregulation of complement type 3 receptors when compared with rats receiving only glucocorticoids. Compared with the control, cellular proliferation continued in rats given glucocorticoid injection as indicated by the occurrence of many bromodeoxyuridine-labelled cells in the corpus callosum at the age of 6 days. Ultrastructural studies confirmed the presence of mitotic cells identified as amoeboid microglia because of their labelling with isolectin. A striking ultrastructural feature in glucocorticoids-injected rats was the wide occurrence of amoeboid microglial cells that had ingested a variable number of lectin-labelled cells. It is concluded from this study that the drastic reduction of amoeboid microglia after glucocorticoid injections can be attributed to the suppression of their precursor cells, monocytes. Another possible explanation is the acceleration of their degeneration process, probably greatly enhanced by glucocorticoids; the degenerating amoeboid microglia were readily eliminated by the surviving amoeboid microglial cells through endocytosis. Glucocorticoids also accelerated the maturation process of the persisting amoeboid microglia to become ramified in form.

Animals↗
PubMed1996

Swift transformation and locomotion of polymorphonuclear leukocytes and microglia as observed by VEC-DIC microscopy (video microscopy).

The detailed assembly used by us for video-enhanced contrast-differential interference contrast (VEC-DIC) microscopy (video microscopy is first described. Employing such video microscopy, we then examined the morphological changes occurring during locomotion and activation processes of polymorphonuclear leukocytes (PMNL) and microglia at an almost electron microscopic magnification. Upon contacting the substratum, PMNL transformed into a polarized ameboid shape and crawled extending pseudopodia, as has been well documented previously. The PMNL sometimes displayed a peculiar locomotion as if they were stepping on "tiny legs", or sliding on a treadmill of cell membrane. Cultured microglia were observed to exist in 4 forms; ramified, reactive, villous, and ameboid. Microglia in the reactive form pivoted, circled and crawled on the astroglial cell layer using their transparent lamellipodia with no morphological changes in their cell body. Unlike PMNL, reactive microglia exhibited no agitated movements of their intracellular organelles, including granules and cytosol, during locomotion. Lamellipodia on the undersurface of the cell body touching the cell layer adhesively, appeared to serve as the locomotive apparatus. When activated, both floating PMNL and microglia of villous form assumed an ameboid shape within a few seconds. Microglia occasionally swam in the medium waving their lamellipodia towards a target object (e.g. zymosan A particles), remodelling to an amorphous ameboid form and covering up the target. We attempt to discuss such swift morphological changes from the standpoint of thermodynamic potential of Gibbs free energy which is stored within the cells.

Cell Movement↗
PubMed2003

Role of antiproliferative B cell translocation gene-1 as an apoptotic sensitizer in activation-induced cell death of brain microglia.

Mouse brain microglial cells undergo apoptosis on exposure to inflammatory stimuli, which is considered as an autoregulatory mechanism to control their own activation. Here, we present evidence that an antiproliferative B cell translocation gene 1 (BTG1) constitutes a novel apoptotic pathway of LPS/IFN-gamma-activated microglia. The expression of BTG1 was synergistically enhanced by LPS and IFN-gamma in BV-2 mouse microglial cells as well as in primary microglia cultures. Levels of BTG1 expression inversely correlated with a proliferative capacity of the microglial cells. Tetracycline-based conditional expression of BTG1 not only suppressed microglial proliferation but also increased the sensitivity of microglial cells to NO-induced apoptosis, suggesting a novel mechanism of cooperation between LPS and IFN-gamma in the induction of microglial apoptosis. An increase in BTG1 expression, however, did not affect microglial production of NO, TNF-alpha, or IL-1beta, indicating that the antiproliferative BTG1 is important in the activation-induced apoptosis of microglia, but not in the activation itself. The synergistic action of LPS and IFN-gamma in the microglial BTG1 induction and apoptosis was dependent on the Janus kinase/STAT1 pathway, but not IFN-regulatory factor-1, as demonstrated by a pharmacological inhibitor of Janus kinase (AG490), STAT1 dominant negative mutant, and IFN-regulatory factor-1-deficient mice. Taken together, antiproliferative BTG1 may participate in the activation-induced cell death of microglia by lowering the threshold for apoptosis; BTG1 increases the sensitivity of microglia to apoptogenic action of autocrine cytotoxic mediator, NO. Our results point out an important link between the proliferative state of microglia and their sensitivity to apoptogenic agents.

Amino Acid Sequence↗
PubMed2003

Microglia-mediated nitric oxide cytotoxicity of T cells following amyloid beta-peptide presentation to Th1 cells.

Alzheimer's disease is marked by progressive accumulation of amyloid beta-peptide (Abeta) which appears to trigger neurotoxic and inflammatory cascades. Substantial activation of microglia as part of a local innate immune response is prominent at sites of Abeta plaques in the CNS. However, the role of activated microglia as Abeta APCs and the induction of adaptive immune responses has not been investigated. We have used primary microglial cultures to characterize Abeta-Ag presentation and interaction with Abeta-specific T cells. We found that IFN-gamma-treated microglia serve as efficient Abeta APCs of both Abeta1-40 and Abeta1-42, mediating CD86-dependent proliferation of Abeta-reactive T cells. When cultured with Th1 and Th2 subsets of Abeta-reactive T cells, Th1, but not Th2, cells, underwent apoptosis after stimulation, which was accompanied by increased levels of IFN-gamma, NO, and caspase-3. T cell apoptosis was prevented in the presence of an inducible NO synthase type 2 inhibitor. Microglia-mediated proliferation of Abeta-reactive Th2 cells was associated with expression of the Th2 cytokines IL-4 and IL-10, which counterbalanced the toxic levels of NO induced by Abeta. Our results demonstrate NO-dependent apoptosis of T cells by Abeta-stimulated microglia which may enhance CNS innate immune responses and neurotoxicity in Alzheimer's disease. Secretion of NO by stimulated microglia may underlie a more general pathway of T cell death in the CNS seen in neurodegenerative diseases. Furthermore, Th2 type T cell responses may have a beneficial effect on this process by down-regulation of NO and the proinflammatory environment.

Amyloid beta-Peptides↗
PubMed2006

Different neurotropic pathogens elicit neurotoxic CCR9- or neurosupportive CXCR3-expressing microglia.

What mechanism that determines microglia accomplishing destructive or constructive role in CNS remains nebulous. We report here that intracranial priming and rechallenging with Toxoplasma gondii in mice elicit neurotoxic CCR9+ Irg1+ (immunoresponsive gene 1) microglia, which render resistance to apoptosis and produce a high level of TNF-alpha; priming and rechallenging with lymphocytic choriomeningitis virus elicit neurosupportive CXCR3+ Irg1- microglia, which are sensitive to apoptosis and produce a high level of IL-10 and TGF-beta. Administration of CCR9 and/or Irg1 small interfering RNA alters the frequency and functional profiles of neurotoxic CCR9+ Irg1+ and neurosupportive CXCR3+ Irg1- microglia in vivo. Moreover, by using a series of different neurotropic pathogens, including intracellular parasites, chronic virus, bacteria, toxic substances, and CNS injury to intracranially prime and subsequent rechallenge mice, the bi-directional elicitation of microglia has been confirmed as neurotoxic CCR9+ Irg1+ and neurosupportive CXCR3+ Irg1- cells in these mouse models. These data suggest that there exist two different types of microglia, providing with a novel insight into microglial involvement in neurodegenerative and neuroinflammatory pathogenesis such as Alzheimer's disease and AIDS dementia.

Animals↗
PubMed1999

Mechanisms of IL-10 production in human microglia-T cell interaction.

IL-10, a cytokine with important anti-inflammatory properties, is generated within the CNS during neuroinflammation. The mechanism for its production is poorly understood. Since infiltrating lymphocytes come into close proximity with the macrophage-like cells of the CNS, the microglia, we have used an in vitro human microglia-T cell coculture system to address the mechanisms of IL-10 production. We demonstrate that microglia or activated T cells alone secrete negligible amounts of IL-10, but that their coculture results in significant IL-10 production, which was effected by both cell types. IL-10 generation was cell contact dependent, and treatment with anti-CD40, CTLA-4-Fc, or anti-CD23 decreased the IL-10 content in microglia-T cell cocultures. The combination of anti-CD40 and CTLA-4-Fc reduced IL-10 levels to the negligible amounts seen with T cells or microglia in isolation. By also measuring TNF-alpha levels, specificity of cytokine regulation was observed; while anti-CD40 and CTLA-4-Fc reduced IL-10 and TNF-alpha levels, anti-CD23 did not affect TNF-alpha while attenuating IL-10 generation. Anti-very late Ag-4, which decreased TNF-alpha levels, did not affect IL-10. These results implicate the CD40, B7, and CD23 pathways in IL-10 production following microglia-T cell encounter and have relevance to the regulation of an anti-inflammatory response within the CNS.

Abatacept↗
PubMed2001

Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia.

Minocycline, a semisynthetic tetracycline derivative, protects brain against global and focal ischemia in rodents. We examined whether minocycline reduces excitotoxicity in primary neuronal cultures. Minocycline (0.02 microm) significantly increased neuronal survival in mixed spinal cord (SC) cultures treated with 500 microm glutamate or 100 microm kainate for 24 hr. Treatment with these excitotoxins induced a dose-dependent proliferation of microglia that was associated with increased release of interleukin-1beta (IL-1beta) and was followed by increased lactate dehydrogenase (LDH) release. The excitotoxicity was enhanced when microglial cells were cultured on top of SC cultures. Minocycline prevented excitotoxin-induced microglial proliferation and the increased release of nitric oxide (NO) metabolites and IL-1beta. Excitotoxins induced microglial proliferation and increased the release of NO metabolites and IL-1beta also in pure microglia cultures, and these responses were inhibited by minocycline. In both SC and pure microglia cultures, excitotoxins activated p38 mitogen-activated protein kinase (p38 MAPK) exclusively in microglia. Minocycline inhibited p38 MAPK activation in SC cultures, and treatment with SB203580, a p38 MAPK inhibitor, but not with PD98059, a p44/42 MAPK inhibitor, increased neuronal survival. In pure microglia cultures, glutamate induced transient activation of p38 MAPK, and this was inhibited by minocycline. These findings indicate that the proliferation and activation of microglia contributes to excitotoxicity, which is inhibited by minocycline, an antibiotic used in severe human infections.

Animals↗
PubMed2002

Microglia-Müller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration.

Activation of microglia commonly occurs in response to a wide variety of pathological stimuli including trauma, axotomy, ischemia, and degeneration in the CNS. In the retina, prolonged or high-intensity exposure to visible light leads to photoreceptor cell apoptosis. In such a light-reared retina, we found that activated microglia invade the degenerating photoreceptor layer and alter expression of neurotrophic factors such as nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF). Because these neurotrophic factors modulate secondary trophic factor expression in Müller glial cells, microglia-Müller glia cell interaction may contribute to protection of photoreceptors or increase photoreceptor apoptosis. In the present study, we demonstrate the possibility that such functional glia-glia interactions constitute the key mechanism by which microglia-derived NGF, brain-derived neurotrophic factor (BDNF), and CNTF indirectly influence photoreceptor survival, although the receptors for these neurotrophic factors are absent from photoreceptors, by modulating basic fibroblast growth factor (bFGF) and GDNF production and release from Müller glia. These observations suggest that microglia regulate the microglia-Müller glia-photoreceptor network that serves as a trophic factor-controlling system during retinal degeneration.

Animals↗
PubMed2003

Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway.

The presence of tangles of abnormally phosphorylated tau is a characteristic of Alzheimer's disease (AD), and the loss of synapses correlates with the degree of dementia. In addition, the overexpression of interleukin-1 (IL-1) has been implicated in tangle formation in AD. As a direct test of the requirement for IL-1 in tau phosphorylation and synaptophysin expression, IL-1 actions in neuron-microglia cocultures were manipulated. Activation of microglia with secreted beta-amyloid precursor protein or lipopolysaccharide elevated their expression of IL-1alpha, IL-1beta, and tumor necrosis factor alpha (TNFalpha) mRNA. When such activated microglia were placed in coculture with primary neocortical neurons, a significant increase in the phosphorylation of neuronal tau was accompanied by a decline in synaptophysin levels. Similar effects were evoked by treatment of neurons with recombinant IL-1beta. IL-1 receptor antagonist (IL-1ra) as well as anti-IL-1beta antibody attenuated the influence of activated microglia on neuronal tau and synaptophysin, but anti-TNFalpha antibody was ineffective. Some effects of microglial activation on neurons appear to be mediated by activation of p38 mitogen-activated protein kinase (p38-MAPK), because activated microglia stimulated p38-MAPK phosphorylation in neurons, and an inhibitor of p38-MAPK reversed the influence of IL-1beta on tau phosphorylation and synaptophysin levels. Our results, together with previous observations, suggest that activated microglia may contribute to neurofibrillary pathology in AD through their production of IL-1, activation of neuronal p38-MAPK, and resultant changes in neuronal cytoskeletal and synaptic elements.

Amyloid beta-Protein Precursor↗
PubMed2003

Cell type-specific roles for tissue plasminogen activator released by neurons or microglia after excitotoxic injury.

Tissue plasminogen activator (tPA) plays important roles in the brain after excitotoxic injury. It is released by both neurons and microglia and mediates neuronal death and microglial activation. Mice lacking tPA are resistant to excitotoxicity and show very limited microglial activation. Activated microglia are neurotoxic in culture, but this phenomenon is not well documented in vivo. To further understand the sequence of events through which tPA mediates microglial activation and neurodegeneration, we have generated mice that exhibit restricted expression of tPA through introduction of tPA transgenes under the control of neuronal- or microglial-specific promoters into tPA-deficient mice. Neither strain of transgenic mice shows abnormal brain morphology or inflammation in the absence of injury, and unilateral intrahippocampal kainate injections into the transgenic mice induced excitotoxicity and microglial activation reminiscent of wild-type mice. However, there are differences in the kinetics of the resulting pathology. The neuronal tPA-expressing mice exhibit accelerated microglial activation compared with wild-type or microglial tPA-expressing mice. However, microglial tPA-expressing mice exhibit greater neurodegeneration. These data suggest a model in which tPA plays different roles after kainate injection depending on whether it is released by neurons or microglia. We propose that tPA, initially secreted from injured neurons, acts as a cytokine to activate microglia at the site of injury. These activated microglia then secrete additional tPA, which promotes extracellular matrix degradation, neurodegeneration, and self-proliferation. We suggest that an approach to attenuate microglia-mediated neuronal death in vivo might be to pharmacologically prevent microglial activation.

Animals↗
PubMed2006

ATP receptors of microglia involved in pain.

Microglia, activated when physiological homeostasis is threatened, play an important role as immune cells in the CNS. Activated microglia show a progressive series of changes in morphology, gene expression, function and number, and produce and release various chemical mediators, including proinflammatory cytokines that can produce immunological actions and modify neuronal function. Recently, accumulating evidence has indicated an important role for ATP receptors of activated microglia in neuropathic pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, cancer, diabetes or infection. The expression of the P2X4 receptor, a subtype of ATP receptors, is enhanced in spinal microglia in a peripheral nerve injury model, and blocking pharmacologically and suppressing molecularly P2X4 receptors produces a reduction of the neuropathic pain. Several cytokines such as interleukin 6 (IL6) and tumour necrosis factor alpha (TNFalpha) in the dorsal horn are also increased after nerve lesion and have been implicated in contributing to nerve-injury pain. ATP can activate mitogen-activated protein kinase (MAPK) leading to the release of bioactive substances including cytokines from microglia. Thus, diffusible factors released from activated microglia by the stimulation of purinergic receptors may have an important role in the development of neuropathic pain.

Adenosine Triphosphate↗
PubMed1995

Cryptococcus neoformans survive and replicate in human microglia.

BACKGROUND: Cryptococcus neoformans (CN) is an opportunistic pathogen that can cause fatal meningoencephalitis in patients with immune deficiency. Among the central nervous system (CNS) cells that are infected by CN are perivascular microglia and macrophages. Little is known about the interaction of CN and CNS phagocytes at the cellular level. EXPERIMENTAL DESIGN: To better understand the fate of CN in microglia, we followed Ab-opsonized CN in human fetal microglial culture by phase-contrast microscopy, combined lighted microscopy and transmission electron microscopy of plastic-embedded monolayers, and immunocytochemistry for localization of capsular Ag. RESULTS: Phase-contrast microscopy revealed that microglia initially internalized and contained Ab-opsonized yeast cells within phagolysosomes. However, CN escaped from microglia and resumed extracellular growth 16 to 24 hours after being phagocytosed. Transmission electron microscopy/1-mu epoxy sections revealed that intracellular CN were localized in two types of phagosomes in microglia: spacious phagosomes (SP) and close-fitting phagosomes (CP). Three lines of evidence indicate that SP are the primary sites for intracellular CN survival and replication: (a) SP contained multiple, budding yeast cells, whereas CP contained only single yeast cells within a tightly bound phagosomal membrane; (b) the number of SP and the number of CN within SP increased considerably at 24 hours compared with at 2 hours; and (c) microglial cultures challenged with heat- or amphotericin B-treated CN had significantly fewer SP than those challenged with live CN. Both SP and CP phagosomes fused with lysosomes, suggesting that CN survival in SP was not due to failure of phagolysosomal fusion. In SP, there was attenuation and diffusion of capsular polysaccharide within the phagosome, whereas in CP the fungal capsules remained compact and homogeneous. Immunocytochemistry with an mAb directed to capsular glucoronoxylomannan supported continued synthesis of polysaccharide within SP. CONCLUSION: The results suggest that, in human microglia, CN survive and replicate within SP. Modification of CN capsular polysaccharide within SP may be a contributing factor to this aberrant microglial-CN interaction.

Animals↗
PubMed1995

Immunocytochemical localization of protein kinases Yes and Src in amoeboid microglia in culture: association of Yes kinase with vimentin intermediate filaments.

Amoeboid microglia isolated from primary cultures of neonatal rat brain correspond to a transient form of activated microglia, a resident population of macrophage-like cells. In order to understand the molecular aspects of microglial activation, we have studied amoeboid microglia in primary culture for the presence of Yes and Src protein tyrosine kinases, two kinases which have been implicated in signal transduction process during monocyte/macrophage activation. Immunofluorescence with an antibody raised against the peptide from unique N-terminal domains of Yes and Src demonstrated that Yes and Src kinases are enriched in perinuclear areas of amoeboid microglia. In addition, the antibody to c-yes peptide had a cytoplasmic distribution which coincided with the distribution of vimentin-containing intermediate filaments. Preadsorption of anti-c-yes antibody with an excess of antigenic peptide inhibited anti-c-yes immunofluorescence, while vimentin immunofluorescence remained unchanged. Double immunofluorescence images analyzed with the two-dimensional intensity distribution program (2-D scattered histograms) on Zeiss confocal scanning laser microscope demonstrate the colocalization of c-yes with vimentin. The extent of colocalization was more prominent after exposure of intact cultured microglia to dibutyryl cyclic AMP (dBcAMP), or to phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) or to okadaic acid, an inhibitor of protein phosphatases. The findings suggest that vimentin might serve as molecular support for Yes kinase and, since previous studies have shown that vimentin in amoeboid microglia is one of the major protein substrates of serine/threonine protein kinases, this function could be regulated by phosphorylation.

Animals↗
PubMed1996

Do microglia arise from pericytes? An ultrastructural and distribution study in the rat cerebellar cortex.

Both pericytes and microglia are dark cells that may present similar ultrastructure as well as organization of the rough endoplasmic reticulum cisternae; in addition, images that suggest pericytes being released from the basal lamina compartment, some of them looking like forms of perivascular microglia, may be found. Anatomical articulations between pericytes and microglia are observed. A distribution analysis reveals that, in the considered five neocerebellar cortical strata, the percentage of pericytes preponderates over the percentage of microglia; furthermore, there is a highly statistically significant linear trend between the percentages of pericytes and of microglia in connection with their distribution along the cortical strata. This study suggests that, in rat cerebellar cortex, microglia may arise from pericytes. It is also hypothesized that astroglia have an active role in releasing pericytes from the vascular wall.

Animals↗
PubMed1997

Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1alpha+ microglia and S100beta+ astrocytes with neurofibrillary tangle stages.

Activated microglia, overexpressing interleukin-1 (IL-1), and activated astrocytes, overexpressing S100beta, have been implicated in the formation and evolution of tau2-immunoreactive (tau2+) neuritic plaques in Alzheimer disease. In this study, we assessed the role of IL-1alpha+ microglia and S100beta+ astrocytes in the pathogenesis of another cardinal histopathological feature of Alzheimer disease: tau2+ neurofibrillary tangles. Four distinct stages of neurofibrillary tangle formation were identified: neurons with granular perikaryal tau2 immunoreactivity (stage 0); fibrillar neuronal inclusions (stage 1); dense, neuronal soma-filling inclusions (stage 2); and acellular, fibrillar deposits (stage 3, "ghost tangles"). The numbers of tangles in randomly selected fields of parahippocampal cortex from 11 Alzheimer patients correlated with both the numbers of IL-1alpha+ microglia and the numbers of S100beta+ astrocytes in these fields (r = 0.72, p < 0.02; r = 0.73, p = 0.01, respectively). There were progressive increases in frequency of association between tangle stages and both IL-1alpha+ microglia and S100beta+ astrocytes: 48, 56, 67, and 92% of stage 0-3 tangles, respectively, had associated IL-1alpha+ microglia; and 21, 37, 55, and 91% of stage 0-3 tangles had associated S100beta+ astrocytes. This progressive association of activated IL-1alpha+ microglia and activated S100beta+ astrocytes with tau2+ tangle stages suggests a role for glial-neuronal interactions in the degeneration of tangle-bearing neurons in Alzheimer disease.

Aged↗
PubMed1997

IL-12 production by central nervous system microglia is inhibited by astrocytes.

IL-12, a 75-kDa heterodimeric cytokine composed of two chains (p35 and p40), is a central regulator of immune responses and may be implicated in the pathogenesis of certain inflammatory diseases of the central nervous system (CNS). We have examined the capacity of two CNS APC, microglia and astrocytes, to produce IL-12 upon stimulation with cytokines, LPS, or a neurotropic virus. In purified microglial cultures from neonatal mouse brains, expression of IL-12 p35 and p40 mRNA is induced by LPS and is stimulated maximally by combined IFN-gamma/LPS treatment, as detected by semiquantitative reverse-transcriptase PCR. LPS induces secretion of IL-12 p40, but not of IL-12 p75, as detected by specific ELISA. Combined stimulation with IFN-gamma/LPS enhances IL-12 p40 secretion and induces IL-12 p75 secretion by microglia. Conversely, mouse astrocytes do not express IL-12 p35 mRNA and do not secrete IL-12 p75 under any condition tested. IL-12 production by activated microglia is inhibited by IL-10, PGE2, and cAMP-elevating agents. Coculture of microglia with astrocytes or exposure of microglia to astrocyte-conditioned medium also results in marked reduction of IL-12 p75 and p40 secretion by IFN-gamma/LPS-stimulated microglia, indicating a regulatory role of astrocytes on IL-12 production. This novel mechanism of IL-12 regulation may play an important role in the control of immune responses during infection or in Th1 cell-mediated autoimmune diseases of the CNS.

Animals↗
PubMed1998

The comparison of microglia maturation in different structures of the human nervous system.

The aim of the study was to find out whether differences in morphology and time-sequence of microglia appearance in course of development of the phylogenetically different structures of the central nervous system (CNS) in normal human fetus do exist. An attempt was also made to evaluate quantitatively the development of microglial cells in comparison to astroglia, taking into account their role in the structural and immunological maturation of the CNS. The study was performed on CNS tissue of frontal lobes, mesencephalon and cerebellum from 72 fetuses between 8 and 22 week of gestation (GW). Histochemical and immunohistochemical reactions were used as basic study methods. A quantitative evaluation of developing microglia and astroglia in all investigated structures was performed by counting the mean number of cells per 1 mm2. Morphological and ultrastructural patterns of the three basic types of microglia; ameboid, ramified active and ramified resting, were characterized. It was indicated that they emerge at the same time in all structures under study, except the ameboid microglia arising earlier in the mesencephalon. A quantitative evaluation revealed that the number of ameboid microglial cells decreased slightly in an early stage of fetal development. The number of ramified microglial cells between 11 and 22 GW increased in all structures. The highest values of ramified microglia were found in mesencephalon, and the lowest in white matter of cerebellum. The number of astroglial cells exceeded the increase in ramified microglia by several times in all structures.

Brain↗
PubMed1999

CD40-CD154 interaction and IFN-gamma are required for IL-12 but not prostaglandin E2 secretion by microglia during antigen presentation to Th1 cells.

IL-12 and PGE2 promote and inhibit, respectively, the development of Th1 responses. Production of these mediators by APC residing in the central nervous system (CNS) may be involved in the local regulation of the T cell phenotype during infectious and autoimmune CNS diseases. In the present study we have examined IL-12 and PGE2 secretion by cultured microglia and astrocytes from the mouse brain upon Ag-dependent interaction with I-Ad-restricted, OVA323-339 specific TCR transgenic Th1 and Th2 cell lines. We show that microglia, which restimulate efficiently both Th1 and Th2 cells, secrete IL-12 upon Ag-dependent interaction with Th1, but not with Th2 cells. Th1-driven IL-12 production depends on TCR ligation by MHC class II/peptide complexes, CD40 engagement on microglia, and IFN-gamma secretion by activated Th1 cells. Th1 and, to a lesser extent, Th2 cells also stimulate the production of PGE2 by microglia. T cell-mediated induction of PGE2 requires MHC class II/peptide/TCR interactions but does not depend on CD40 engagement or on the presence of IFN-gamma. Astrocytes, which preferentially activate Th2 cells, fail to produce IL-12 and secrete negligible amounts of PGE2 upon interaction with either Th1 or Th2 cells. These results suggest that during CNS infection or immunopathology, IL-12 produced by microglia upon Ag-specific interaction with Th1 cells may further skew the immune response to Th1, whereas the T cell-dependent production of PGE2 by microglia may represent a negative feedback mechanism, limiting the propagation of Th1 responses.

Animals↗