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PubMed1997

Transforming growth factor-beta1 in adult human microglia and its stimulated production by interleukin-1.

Ameboid microglia express human immunodeficiency virus 1 (HIV-1) more frequently than do ramified microglia. These two microglial subtypes might also differ in the frequency with which they express transforming growth factor-beta1 (TGF-beta1), a cytokine that regulates HIV-1 expression in monocytes. Results described here show that ameboid and ramified microglia express TGF-beta1. In brain tissues from HIV-1-infected individuals as compared with seronegative controls, ameboid rather than ramified microglia more frequently expressed TGF-beta1. Ameboid microglia, isolated and cultured from postmortem adult human brain more frequently expressed TGF-beta1 in presence of interleukin-1(IL-1), a cytokine that is elevated in brains of HIV-1-infected individuals when compared with seronegative controls. The stimulation of TGF-beta1 by IL-1 was dose and time dependent, occurring with ameboid microglia isolated from either frontal cortex or globus pallidus but not midbrain pons. Ameboid microglia are similar to the RCA-1-positive cells that form clusters, called microglial nodules, in the brain of HIV-1-infected individuals. Pathologic conditions, such as disseminated microglial nodules, are associated with HIV-1 encephalitis, direct infection of the brain, and moderate to severe neurologic impairment. TGF-beta1 expression in ameboid microglia may play a role in HIV-1 neuropathogenesis.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Altered immunoexpression of microglia and macrophages after mild head injury.

In this study we examined the temporal response of microglia and macrophages to mild head injury in the rat. Microglia and macrophages were identified by their distinct morphology and by immunophenotype. With regard to the latter, antibodies to OX42 and ED1 were used to define microglia and macrophages, respectively. Although there was no change in the morphology of brain macrophages after mild head injury, the morphology of microglia was dramatically altered. Microglial cell bodies appeared larger with a more elaborate arborization of cellular processes. After head injury certain populations of macrophages and microglia were more intensely immunostained. By 3 days postinjury these intensely stained cells exhibited a characteristic distribution in the brain. Prominently stained microglia were detected in the thalamus, hippocampus, lateral and medial geniculate body, and the substantia nigra. Intensely stained macrophages were located primarily in the cortex and subarachnoid space adjacent to the site of impact. By 7 days postinjury intensely immunostained macrophages and microglia were widespread throughout the injured cortex. These results demonstrate that microglia and macrophages are sensitive to mild head injury. Early changes in the macrophage population are more directly correlated with the most damaged tissue and may reflect migration of these cells from either the subarachnoid space or across the damaged blood-brain barrier. The early widespread microglial response in regions exhibiting no overt neuronal cell damage suggests that these cells are responding to more subtle factor(s) that are expressed in the mildly traumatized brain.

Animals↗

PubMed1999

Differential activation of microglia after experimental spinal cord injury.

This study sought to experimentally clarify time-dependent, differential microglial activation at various spinal cord locations in response to injury. The spinal cords of Wistar rats were either sharply transected at the Th 11 or subjected to compression at the same site. Immediately to 4 weeks after injury, each spinal cord was fixed and cut into longitudinal frozen sections, and was immunostained with OX42 for resident and activated microglia, OX-6 for activated microglia, GFAP for activated astrocytes, and biotinylated BS-I, a lectin for both resident and activated microglia. From three to 24 hours after injury, we observed a narrow belt around the transection site in which OX42 positive microglia were dramatically reduced in number, or often absent. BS-I labeling of the zone disclosed the rapid transformation of those microglia possessing typical antler-like processes to macrophage-like cells. At day 1 and thereafter, the zone of reduced OX42 immunoreactivity was gradually replaced by macrophage-like OX42-positive round cells, and the lesion itself was ultimately capped by fibrogliotic scar tissue. By 2-4 weeks postinjury, another phase of microglial activation was observed in those white matter tracts undergoing Wallerian degeneration. These microglia characterized by the presence of newly-expressed MHC class II antigens. We posit that the decreased OX42 immunoreactivity suggests that CR3 is quickly saturated by activated iC3b and internalized, but not down-regulated. The trigger for this transformation most likely occurs through signaling by iC3b-saturated CR3. In contrast, microglia activation along those degenerating tracts undergoing Wallerian degeneration does not appear to be CR3-related, as the CR3 is upregulated. These observations indicate microglia have at least two different spatial and temporal patterns of activation. One is rapid and most likely involves the blood-borne complement activating system. The other accompanies Wallerian degeneration and is independent of the blood-borne complement system.

Animals↗

PubMed2004

CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE).

The idea that CNS ramified microglia are quiescent has been challenged by studies that show that microglia without the classic signs of activation can be phagocytic and appear with shorter, thicker ramifications. These semi-activated cells may constitute a form of microglia that has not been previously recognized in neuropathological conditions and may contribute to the pathology and dysfunction in these disorders. This study investigated the expression of CD 163, a cell surface marker whose normal expression is restricted to monocytes/macrophages, in cases of HIV or SIV encephalitis (HIVE/SIVE), Alzheimer disease, and variant Creutzfeldt-Jakob disease. In HIVE/SIVE, in addition to reacting with CNS macrophages, CD163 antibody staining was shown to highlight ramified microglia. Such reactivity was especially notable in grey matter ramified microglia and was greater than that of another typically used marker, HLA-DR. CD163 expression was only observed in infected/affected tissue, in contrast to that shown with another microglia marker, GLUT5, which has recently been shown to identify all microglia regardless of disease state. Although activated microglia were present in the other disorders, as evidenced by strong HLA-DR expression, there was very little CD163 immunoreactivity. The activation state identified by CD163 has not been previously recognized and may have a positive or negative impact on neuronal damage shown in HIV-associated dementia.

AIDS Dementia Complex↗

PubMed1994

Effects of ageing on microglia in the normal rat brain: immunohistochemical observations.

The numbers of ramified microglia stained by mouse monoclonal antibodies (OX-6 and X-42) in various regions of the brain were compared in the young (8 weeks) and aged (12 months) rats. OX-6-positive microglia increased in number with ageing, but OX-42-positive microglia did not. In both young and aged rats, the number of OX-6-positive microglia in white matter was higher than that in grey matter, but the number of OX-42-positive microglia in white matter was the same as that in grey matter. OX-42 stains microglia in both activated and resting states, whereas OX-6 stains mainly microglia in the activated state. Our findings suggest that microglia become activated with age-related changes, especially in white matter.

Aging↗

PubMed1993

Morphometric analysis of microglia in Alzheimer's disease.

HLA-DR-immunoreactive microglia were quantitated in the middle temporal gyrus of five late-stage patients with Alzheimer's disease (AD) and five age-matched control subjects using LN3 immunocytochemistry and computerized morphometric image analysis. The grand mean numerical density of HLA-DR-immunoreactive microglia in AD (403.86/mm2) was significantly larger than in the five control subjects (193.33/mm2) (p < 0.0001). The grand mean cross-sectional area of HLA-DR-immunoreactive microglia in AD subjects (222.90 microns2) was significantly larger than in control subjects (121.59 microns2) (p < 0.0001). The percentage of total microglia that were large activated microglia was much greater in AD (47.9%) than in control subjects (15.2%). The grand mean percent of the cortical area occupied by HLA-DR-immunoreactive microglia in AD (9.02%) was significantly greater than in controls (2.35%) (p < 0.0001). Microglia were present in greater numbers in the outer three cortical laminae in both AD and controls. The striking increase in activated microglia in the neocortex and their role in the inflammatory response and possible secretion of neurotoxins could be important in neuron degeneration in AD.

Aged↗

PubMed1998

Microglia and the development of spongiform change in Creutzfeldt-Jakob disease.

Recent in vitro experiments suggest that neurotoxicity of the prion protein is dependent on the presence of microglia. We have studied 11 cases of Creutzfeldt-Jakob disease (CJD) using immunocytochemistry in combination with computerized image analysis to clarify the relationship between spongiform change and microglial activation. MHC class II-positive microglia were almost exclusively confined to cortical gray matter where the neuropil area occupied by these cells exceeded that of controls more than 350-fold. In cortical regions with a bimodal distribution of spongiform degeneration, the presence of class II-positive microglia correlated well with the presence of vacuolation in layer V, but significantly less with spongiform change in layers II and III. In areas where spongiform degeneration affected the entire depth of the cortex, activated microglia were predominantly located in the inner one-half of the cortex or were evenly distributed throughout all cortical laminae. Here, microglia exhibited atypical, tortuous cell processes and occasionally intracytoplasmic vacuoles, suggesting that microglia themselves may become a disease target. Taken together, our results provide indirect evidence against an early causative involvement of microglia in the development of spongiform change. At later stages, however, diseased microglia could produce harmful factors which mediate both astrogliosis and neuronal injury.

Aged↗

PubMed2004

Expression of glucose transporter 5 by microglia in human gliomas.

Our previous studies indicate that glucose transporter 5 (GLUT5) is a microglial marker in routine paraffin sections, and is rarely present in monocytes/macrophages of the peripheral organs. We examined the expression of GLUT5 in 91 cases of human gliomas to characterize the microglial phenotype in glioma tissues. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections using such antibodies as a GLUT5 antibody, two markers for activated microglia: major histocompatibility complex (MHC) class II Ag and macrophage scavenger receptor class A (MSR-A), and MIB-1 antibody. The immunoreactivity of GLUT5 was present in three microglial phenotypes: ramified (resting), activated, and ameboid (macrophagic) microglia in most of the cases. A double-labelling study of astrocytic tumours using GLUT5 and MIB-1 antibodies demonstrated a proportion of proliferating microglia. However, no morphological difference between MIB-1-positive, microglial cells and MIB-1-negative, microglial cells was found. The number of GLUT5-positive microglia was significantly (P < 0.001) higher in astrocytic tumours than in oligodendroglial tumours. Many GLUT5-positive microglia (up to 52% in total cells) were often observed in pilocytic astrocytomas, where microglial cells were predominantly ramified, and the number of MHC class II- or MSR-A-positive microglia was less than GLUT5-positive microglia. Thus, the present study indicated that intrinsic microglia can be a source of microglia/macrophages cell populations in astrocytic tumours, and that pilocytic astrocytomas often have a high proportion of microglial cells with mild activation.

Blotting, Western↗

PubMed2003

Chemokine modulation of high-conductance Ca(2+)-sensitive K(+) currents in microglia from human hippocampi.

During acute pathological processes, microglia transform into an activated state characterized by a defined morphology and current profile, and are recruited to injury sites by chemokines. No information is available on the ion channels and the mode of action of chemokines in microglia in brain slices from humans with a chronic pathology. Thus, patch-clamp recordings of microglia were performed in hippocampal slices from seven patients who underwent surgery for pharmaco-resistant epilepsy. Cells were identified as microglia by positive labelling with fluorescein-conjugated tomato lectin before recording. All the recorded cells had an ameboid morphology characteristic of activated microglia. However, they had a high input resistance (3.6 G omega), a zero-current resting potential of -16 mV, and lacked Na+ currents, inwardly rectifying and delayed rectifying K+ currents such as non-activated microglia. Importantly, recorded cells expressed Ca2+-sensitive outward currents that activated at 0 mV with non-buffered intracellular Ca2+ and were sensitive to 1 mm tetraethylammonium (TEA). The estimated single-channel conductances were 187 pS in cell-attached and 149 pS in outside-out patches, similar to those of high-conductance Ca2+-dependent K+ channels. The chemokine MIP1-alpha increased whole-cell outward current amplitudes measured at +60 mV by a factor of 3.3. Thus, microglia in hippocampi from epileptic patients express high-conductance Ca2+-dependent K+ channels that are modulated by the chemokine MIP1-alpha. This modulation may contribute to the migratory effect of MIP1-alpha on microglia.

Calcium↗

PubMed2002

MHC gene related effects on microglia and macrophages in experimental autoimmune encephalomyelitis determine the extent of axonal injury.

Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats is a chronic inflammatory demyelinating disease of the central nervous system (CNS) strongly mimicking multiple sclerosis (MS). We determined the involvement of macrophages and microglia in the lesions of MOG-EAE in relation to different major histocompatibility complex (MHC, RT1 in rat) haplotypes. We used intra-RT1 recombinant rat strains with recombinations between the RT1a and RT1u haplotypes on the disease permissive LEW non-MHC genome. Activated microglia and macrophages were identified morphologically and by expression of ED1 and allograft inhibitory factor-1 (AIF-1), and differentiated by their morphological phenotype. White matter lesions contained more macrophages and less microglia compared to grey matter lesions. Similarly active lesions were mainly infiltrated by macrophages, while microglia were abundant in inactive demyelinated plaques. In addition, we found a highly significant genetic association between a macrophage or microglia dominated lesional phenotype, which was independent from location and activity of the lesions. This was not only the case in demyelinating plaques of chronic EAE, but also in purely inflammatory lesions of acute passive transfer EAE. Rat strains with an u-haplotype in both the Class II and the telomeric non-classical Class I region revealed inflammatory and demyelinating lesions, which were dominated by activated microglia. The a-haplotype in any of these regions was associated with macrophage dominated lesions. A comparison of lesions, exactly matched for stages of demyelinating activity in these different rat strains, showed that in spite of a similar extent of demyelination, axonal injury was significantly less in microglia compared to macrophage dominated lesions. Thus, our studies document a genetic influence of the MHC-region on the relative contribution of macrophages versus microglia in the pathogenesis of EAE.

Animals↗

PubMed2006

Activation of microglia by borna disease virus infection: in vitro study.

Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to the certain neuronal populations. Since persistent BDV infection of neurons in vitro is noncytolytic and noncytopathic, activated microglia have been suggested to be responsible for neuronal cell death in vivo. However, the mechanisms of activation of microglia in neonatally BDV-infected rat brain have not been investigated. To address these issues, activation of primary rat microglial cells was studied following exposure to purified BDV or to persistently BDV-infected primary cortical neurons or after BDV infection of primary mixed neuron-glial cultures. Neither purified virus nor BDV-infected neurons alone activated primary microglia as assessed by the changes in cell shape or production of the proinflammatory cytokines. In contrast, in the BDV-infected primary mixed cultures, we observed proliferation of microglia cells that acquired the round morphology and expressed major histocompatibility complex molecules of classes I and II. These manifestations of microglia activation were observed in the absence of direct BDV infection of microglia or overt neuronal toxicity. In addition, compared to uninfected mixed cultures, activation of microglia in BDV-infected mixed cultures was associated with a significantly greater lipopolysaccharide-induced release of tumor necrosis factor alpha, interleukin 1beta, and interleukin 10. Taken together, the present data are the first in vitro evidence that persistent BDV infection of neurons and astrocytes rather than direct exposure to the virus or dying neurons is critical for activating microglia.

Animals↗

PubMed2006

Anti-CD45RO suppresses human immunodeficiency virus type 1 replication in microglia: role of Hck tyrosine kinase and implications for AIDS dementia.

Macrophages and microglia are productively infected by HIV-1 and play a pivotal role in the pathogenesis of AIDS dementia. Although macrophages and microglia express CD45, a transmembrane protein tyrosine phosphatase, whether modulation of its activity affects human immunodeficiency virus type 1 (HIV-1) replication is unknown. Here, we report that of the five human CD45 isoforms, microglia express CD45RB and CD45RO (RB > RO) and treatment of microglia with a CD45 agonist antibody alphaCD45RO (UCHL-1) inhibits HIV-1 replication. alphaCD45RO prevented HIV-1 negative factor (Nef)-induced autophosphorylation of hematopoietic cell kinase (Hck), a myeloid lineage-specific Src kinase. Recombinant CD45 protein also inhibited HIV-1-induced Hck phosphorylation in microglia. Antennapedia-mediated delivery of Hck Src homology domain 3 (SH3), a domain that binds to the Nef PxxP motif with high affinity, reduced HIV-1-induced Hck phosphorylation and HIV-1 production in microglia. HIV-1-induced LTR transactivation was observed in U38 cells stably overexpressing wild-type Hck but not kinase-inactive Hck. In microglia, alphaCD45RO reduced activation of transcription factors (NF-kappaB and CCAAT enhancer binding protein) necessary for LTR transactivation in macrophages. These results establish that in myeloid lineage cells, Nef interacts with the Hck SH3 domain, resulting in autophosphorylation of Hck and an increase in HIV-1 transcription. alphaCD45RO-mediated inhibition of HIV-1 replication in microglia identifies the CD45 protein tyrosine phosphatase as a potential therapeutic target for HIV-1 infection/AIDS dementia.

AIDS Dementia Complex↗

PubMed1995

Flow cytometric identification of a minority population of MHC class II positive cells in the normal rat retina distinct from CD45lowCD11b/c+CD4low parenchymal microglia.

AIMS: This study aimed to isolate and classify by flow cytometry, the cell surface phenotype of microglia in the normal rat retina with a view to identifying putative antigen presenting cells (APC) within the retina, which has to date not been possible by immunohistochemistry. METHODS: Normal rat retinal microglia were isolated and classified using a modification of an isolation technique employing graduated Percoll density gradient cell separation and flow cytometric phenotypic criteria used for CNS microglia. RESULTS: Retinal microglia can be defined by flow cytometry on the basis of their CD45lowCD11b/c+CD4low cell surface expression. Constitutive MHC class II expression in the normal rat retina was confined almost exclusively to a very minor population of cells expressing neither low (microglia) nor high levels of CD45. Three colour flow cytometric analysis confirmed that these MHC class II positive cells were ED2+. CONCLUSIONS: Using this sensitive isolation technique we have identified the cell surface characteristics of ramified, resident microglia, and found that they do not constitutively express MHC class II. There is, however, constitutive MHC class II expression on a phenotypically distinct population of cells (CD45low/highED2+). We propose these cells are the counterpart of the perivascular macrophages found in the CNS which present antigen to extravasating T cells, although their exact retinal location can only be confirmed by immunohistochemical analysis. The role of parenchymal microglia as APC remains undefined. Future isolation of microglia and putative perivascular cells using this technique will help identify the role these cells play in the initiation and perpetuation of immune responses within the retina.

Animals↗

PubMed1999

Activation of microglia during developmentally regulated cell death in the cerebral cortex.

Neuronal elimination in the developing CNS is accomplished by an orderly type of cellular suicide called programmed cell death. The principal non-neuronal cells implicated in regulating programmed cell death and subsequent phagocytosis of dying neurons are the brain's macrophage population, the microglia. Little is known about the signaling between microglia and neurons during programmed cell death. However, macrophages in non-neural tissues express receptors for immunoglobulin (IgG) and complement, and these molecules help regulate phagocytosis of dying cells and foreign organisms. Since many of the neurons generated early in CNS development are transient cell types that are immunoreactive for IgG [Upender et al.: J Comp Neurol 1997; 384:271-282], we hypothesized that IgG might alter the phagocytic properties of microglia within the developing nervous system and potentiate engulfment of dying cells. To begin to address this hypothesis, we first asked whether cortical neurons immunoreactive for IgG or calbindin-D28k exhibit morphological evidence of programmed cell death in the cerebral cortex of neonatal rat pups. Secondly, we quantified the incidence of contacts made by microglia on IgG- vs. calbindin-immunoreactive neurons. Thirdly, perturbation experiments were performed to elevate intracortical levels of IgG and the incidence of microglia:neuron contacts were determined. We found that although the nuclei of some IgG-immunoreactive neurons exhibited condensation and fragmentation characteristic of programmed cell death, we did not observe pyknotic calbindin-immunoreactive neurons. IgG-immunoreactive neurons were also more likely to be contacted by microglia than calbindin-immunoreactive neurons. Elevating intracortical levels of IgG experimentally led to a dramatic increase in the expression of microglia complement receptors throughout the cerebral cortex. Taken together, these results suggest that IgG normally present within neuronal subsets in the developing cerebral cortex could serve to locally regulate the expression of complement receptors on microglia.

Animals↗

PubMedDate not supplied

Up-regulation of cytoskeletal proteins in activated microglia.

OBJECTIVES: This study investigates how the tumor necrosis factor (TNF-alpha) and interleukin-1beta (IL-1beta) affect the morphology, organization, and expression of actin, beta-actin and tubulin in microglia. MATERIALS AND METHODS: Microglia cultures were prepared from neopallia of newborn mice. Immunofluorescence, immunoblotting, and ELISA studies were used. RESULTS: When microglia are treated with TNF-alpha, IL-1beta or a combination of both for 1-5 days, the majority change from an ameboid to a large, round and flat shape. F-actin and beta-actin isoform, which are diffusely arranged throughout the cytoplasm before stimulation, are reorganized into filamentous bundles underneath and parallel to the cell membrane, which projects into many ruffles. This organization is maintained even after withdrawal of the cytokines. The dense microtubule network of tubulin in nontreated microglia becomes less dense and extends to occupy the cytoplasm of the treated microglia. Immunoblotting shows that the amount of total actin, beta-actin isoform and tubulin increases in treated microglia. In addition, IL-1beta and a combination of both TNF-alpha and IL-1beta stimulate the release of IL-6 by microglia. CONCLUSION: This study suggests that TNF-alpha and IL-1beta have an effect on the expression of cytoskeletal proteins similar to some extent to that of LPS. The up-regulation of actin, beta-actin and tubulin may play a key role in the motility and recruitment of microglia to the area of central nervous system inflammation.

Actins↗

PubMed2005

Effect of steroidal and non-steroidal drugs on the microglia activation pattern and the course of degeneration in the retinal degeneration slow mouse.

BACKGROUND: In hereditary retinal degeneration, microglia cells become activated, migrate through the outer nuclear layer (ONL) and accumulate in the subretinal space. Although this inflammatory process is not likely to be responsible for the onset of photoreceptor apoptosis, cytotoxic substances secreted by activated microglia could potentially accelerate and perpetuate the degenerative process. Anti-inflammatory drugs have been shown to modulate the microglia response in neurodegenerative disorders and potentially ameliorate the disease progression in various animal model systems. In this study we wanted to test the impact of the most commonly used anti-inflammatory drugs (acetylsalicylate and prednisolone) on the microglia activation pattern, the rate of caspase-3-dependent photoreceptor apoptosis and the course of the degeneration in the retinal degeneration slow (rds) mouse retina. METHODS: 169 pigmented rds mice and 30 CBA wild-type mice were used for this study. The treatment groups were injected daily with either acetylsalicylate (200 mg/kg) or prednisolone (2 mg/kg) i.p. from day 0 up to 3 months. Animals were sacrificed at days 10, 14, 16, 18, 20, 30, 40, 60 and 90. Cryoprotected frozen sections were immunostained with F4/80 and cleaved caspase-3 antibodies. The main outcome measures were the total microglia count in the subretinal space, the total cleaved caspase-3-positive cells in the ONL and the averaged number of photoreceptor rows in the midperipheral retina. RESULTS: Neither acetylsalicylate nor prednisolone reduced subretinal microglia accumulation in the rds mouse degeneration model. Moreover, they aggravated migration and accumulation in the early time course. The apoptotic cascade started earlier and was more pronounced in both treatment groups compared to the control group. The pace of retinal degeneration was not reduced in the treatment groups compared to the untreated control. In contrast, acetylsalicylate did significantly accelerate the photoreceptor cell degeneration in comparison to the prednisolone (p < 0.001) and to the control group (p < 0.001). CONCLUSIONS: Acetylsalicylate and prednisolone do not decrease the microglia response in the rds mouse and are not neuroprotective. More research is needed to clarify the molecular mechanisms which lead to photoreceptor cell death and to elucidate the complex role of microglia in inherited retinal degeneration.

Animals↗

PubMed2005

Development of neonatal murine microglia in vitro: changes in response to lipopolysaccharide and ischemia-like injury.

Hypoxic/ischemic brain injury in the neonate can activate an inflammatory cascade, which potentiates cellular injury. The role of microglia in this inflammatory response has not been studied extensively. We used an in vitro model of murine microglia to investigate changes in microglial cytokine release and injury during early development. Isolated microglia were subjected to lipopolysaccharide (LPS) activation or injury by glucose deprivation (GD), serum deprivation (SD), or combined oxygen-glucose deprivation (OGD) for varying durations. The extent and the type of cell death were determined by trypan blue, terminal deoxynucleotidyl end-nick labeling, and annexin staining. Early-culture microglia (2-3 d in purified culture) showed significantly more apoptotic cell death after SD, GD, and OGD compared with microglia maintained in culture for 14-17 d. Measurements of tumor necrosis factor-alpha (TNF-alpha) and IL-1beta in culture media demonstrated that OGD induced greater release of both TNF-alpha and IL-1beta than LPS activation, with early-culture microglia producing more TNF-alpha compared with late-culture microglia. Microglia that are cultured for a short time are more sensitive to ischemia-like injury in vitro than those that are cultured for longer durations and may contribute to worsening brain injury by increased release of inflammatory cytokines. Inhibition of microglial activation and decreasing proinflammatory cytokine release may be targets for reduction of neonatal hypoxic/ischemic brain injury.

Animals↗

PubMed2002

Reciprocal interactions between microglia and neurons: from survival to neuropathology.

Microglia represent a major cellular component of the brain, where they constitute a widely distributed network of immunoprotective cells. During the last decades, it has become clear that the functions traditionally ascribed to microglia, i.e. to dispose of dead cells and debris and to mediate brain inflammatory states, are only a fraction of a much wider repertoire of functions spanning from brain development to aging and neuropathology. The aim of the present survey is to critically discuss some of these functions, focusing in particular on the reciprocal microglia-neuron interactions and on the complex signaling systems subserving them. We consider first some of the functional interactions dealing with invasion, proliferation and migration of microglia as well as with the establishment of the initial blueprint of neural circuits in the developing brain. The signals related to the suppression of immunological properties of microglia by neurons in the healthy brain, and the derangement from this physiological equilibrium in aging and diseases, are then examined. Finally, we make a closer examination of the reciprocal signaling between damaged neurons and microglia and, on these bases, we propose that microglial activation, consequent to neuronal injury, is primarily aimed at neuroprotection. The loss of specific communication between damaged neurons and microglia is viewed as responsible for the turning of microglia to a hyperactivated state, which allows them to escape neuronal control and to give rise to persistent inflammation, resulting in exacerbation of neuropathology. The data surveyed here point at microglial-neuron interactions as the basis of a complex network of signals conveying messages with high information content and regulating the most important aspects of brain function. This network shares similar features with some fundamental principles governing the activity of brain circuits: it is provided with memory and it continuously evolves in relation to the flow of time and information.

Animals↗