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PubMed2001

Activated microglia in the human glaucomatous optic nerve head.

To investigate the distribution and potential participation of microglia, the resident defense cells of the central nervous system, in the optic nerve head (ONH) in glaucoma, histological paraffin sections of optic nerves from normal and glaucoma patients with mild to advanced nerve damage were studied using double labeling immunohistofluorescence. A monoclonal antibody for HLA-DR, indicating activated microglia, was colocalized with antibodies for functional proteins. In normal ONHs, microglia do not contain TGF-beta2, COX-2, or TNF-alpha and are not positive for PCNA; however, in glaucomatous ONHs, microglia contain abundant TGF-beta2, TNF-alpha, and PCNA. In glaucomatous eyes, a few microglia are usually positive for COX-2. In normal ONHs, there are rarely microglia containing TGF-beta1, NOS-2, TSP, TIMP-2, and CD68, but, in glaucomatous tissue, a few microglia are positive from the prelaminar to the postlaminar regions. MMP-1, MMP-2, MMP-3, and MMP-14 are constitutively present in the perivascular microglia in normal ONHs and appear to be more abundant in glaucomatous tissue. COX-1, TNF-R1, TIMP-1, and c-fms are constitutively present in normal tissues and appear to be increased in microglia in the glaucomatous ONHs. HSP27 is not present in microglia. In glaucomatous ONHs, microglia become activated and phagocytic and produce cytokines, mediators, and enzymes that can alter the extracellular matrix. Our findings suggest that activated microglia may participate in stabilizing the tissue early in the disease process, but, as the severity of the glaucomatous damage increases, the activities of microglia may have detrimental consequences for the pathological course of glaucomatous optic neuropathy.

Aged↗

PubMed1999

The role of microglia and macrophages in the pathophysiology of the CNS.

Microglia are a major ghal component of the central nervous system (CNS) and are extremely sessile. Only a subtype, the perivascular microglia, are regularly replaced from the bone marrow in adult animals. Microglia respond to virtually any, even minor pathological events in the CNS. In most pathological settings microglia are aided by infiltrating hematogenous macrophages. Upon activation microglia and macrophages share most phenotypical markers and can exert similar effector functions. After transection of a CNS fibre tract microglia are insufficiently activated and hematogenous macrophages do not significantly enter the degenerating nerve stump. Thereby myelin debris that contains neurite outgrowth inhibiting activity persists for long time. This is in sharp contrast to the peripheral nervous system in which hematogenous macrophages are rapidly recruited in response to axotomy and clear myelin debris allowing regrowth of axons from the proximal stump. However, CNS lesion paradigms with breakdown of the blood-brain barrier such as cerebral ischemia, brain abscesses and stab wounds elicit prompt microglial activation, macrophage recruitment and debris clearance. There is increasing evidence that microglia play an active part in degenerative CNS diseases. In Alzheimer's disease activated microglia appear to be involved in plaque formation. In experimental globoid cell dystrophy T-cell independent induction of major histocompatibility complex class II molecules on microglia accelerates demyelination. In autoimmune diseases microglia probably have dual functions. Microglia present antigen to infiltrating T cells and exert effector functions thereby locally augmenting immune responses. On the other hand, microglia have the capacity to downregulate T cell responses. In the human acquired immunodeficiency syndrome (AIDS) virus infected macrophages probably introduce the virus to the CNS and in concert with microglia are involved in the pathophysiology of the AIDS dementia complex.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis.

The most common inherited form of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting adult motoneurons, is caused by dominant mutations in the ubiquitously expressed Cu(2+)/Zn(2+) superoxide dismutase (SOD1). Recent studies suggest that glia may contribute to motoneuron injury in animal models of familial ALS. To determine whether the expression of mutant SOD1 (mSOD1(G93A)) in CNS microglia contributes to motoneuron injury, PU.1(-/-) mice that are unable to develop myeloid and lymphoid cells received bone marrow transplants resulting in donor-derived microglia. Donor-derived microglia from mice overexpressing mSOD1(G93A), an animal model of familial ALS, transplanted into PU.1(-/-) mice could not induce weakness, motoneuron injury, or an ALS-like disease. To determine whether expression of mSOD1(G93A) in motoneurons and astroglia, as well as microglia, was required to produce motoneuron disease, PU.1(-/-) mice were bred with mSOD1(G93A) mice. In mSOD1(G93A)/PU.1(-/-) mice, wild-type donor-derived microglia slowed motoneuron loss and prolonged disease duration and survival when compared with mice receiving mSOD1(G93A) expressing cells or mSOD1(G93A) mice. In vitro studies confirmed that wild-type microglia were less neurotoxic than similarly cultured mSOD1(G93A) microglia. Compared with wild-type microglia, mSOD1(G93A) microglia produced and released more superoxide and nitrite+nitrate, and induced more neuronal death. These data demonstrate that the expression of mSOD1(G93A) results in activated and neurotoxic microglia, and suggests that the lack of mSOD1(G93A) expression in microglia may contribute to motoneuron protection. This study confirms the importance of microglia as a double-edged sword, and focuses on the importance of targeting microglia to minimize cytotoxicity and maximize neuroprotection in neurodegenerative diseases.

Aging↗

PubMed1999

Microglia in the optic nerve head and the region of parapapillary chorioretinal atrophy in glaucoma.

BACKGROUND: Microglia, the macrophages and immune surveillance cells of the central nervous system, are quiescent normally but become activated in injured neural tissue. We have determined the distribution and potential participation of microglia in glaucomatous optic nerve degeneration. METHODS: Microglia were localized by immunohistochemistry on paraffin sections of age-matched normal and glaucomatous human eyes obtained within 24 hours after death. Monoclonal and polyclonal antibodies that recognize specific epitopes on microglia and other cell types were localized by immunoperoxidase and immunofluorescence. RESULTS: Stellate cells with thin, ramified processes, positive for HLA-DR and CD45 but negative for glial fibrillary acid protein, were identified as quiescent microglia. These cells were found throughout the normal optic nerve head in the walls of large blood vessels and surrounding capillaries in glial columns and cribriform plates. In glaucomatous eyes with moderate and severe optic nerve head damage, microglia were present as clusters of large ameboid, activated cells in the compressed lamina cribrosa and as formations of concentric circles surrounding blood vessels. In the parapapillary chorioretinal region of glaucomatous optic nerve heads, large, activated microglia were present as single cells or clusters on the termination of the Bruch's membrane. In addition, along the optic nerve/choriocapillaris-scleral interface, activated microglia appeared to form linear arrays near the choriocapillaris vessels. These cells were parenchymal and not in close association with the vasculature. CONCLUSIONS: In glaucoma, microglia in the optic nerve head become activated and redistributed. Enlarged, activated microglia appear in the parapapillary chorioretinal region, perhaps due to migration from the disorganized prelaminar and laminar tissue. Strategically positioned microglia may also serve a neuroprotective function in relation to a damaged blood-retinal barrier. The activity of microglia in the parapapillary chorioretinal region in glaucoma may be responsible for some of the biomicroscopic and histological changes that are associated with parapapillary chorioretinal atrophy.

Aged↗

PubMed1996

Phenotypic diversity and kinetics of proliferating microglia and astrocytes following cortical stab wounds.

Brain injury induces reactive gliosis, characterized by increased expression of glial fibrillary acidic protein (GFAP), astrocyte hypertrophy, and hyperplasia of astrocytes and microglia. One hypothesis tested in this study was whether ganglioside GD3+ glial precursor cells would contribute to macroglial proliferation following injury. Adult rats received a cortical stab wound. Proliferating cells were identified by immunostaining for proliferating cell nuclear antigen (PCNA) and by [3H]-thymidine autoradiography, and cell phenotypes by immunocytochemical staining for GD3, GFAP, ED1 (for reactive microglia) and for Bandeiraea Simplicifolia isolectin-B4 binding (all microglia). Animals were labeled with thymidine at 1,2,3, and 4 days postlesion (dpl) and sacrificed at various times thereafter. Proliferating cells of each phenotype were quantified. A dramatic upregulation of GD3 on ramified microglia was seen in the ipsilateral hemisphere by 2 dpl. Proliferating cells consisted of microglia and fewer astrocytes. Microglia proliferated maximally at 2-3 dpl and one third to one half were GD3+. Astrocytes proliferated maximally at 3-4 dpl, and some were also GD3+. Both ramified and ameboid forms of microglia proliferated and by 4 dpl all GD3+ microglia were ED1+ and vice versa. In the contralateral cortex microglia expressed neither GD3 nor ED1. Thus they acquired these antigens when activated. Neither microglia nor astrocytes that were thymidine-labeled at 2, 3, or 4 dpl changed in number in subsequent days. Most thymidine+ astrocytes were large GFAP+ reactive cells that clearly arose from pre-existing astrocytes, not from GD3+ glial precursors. In this model of injury microglia proliferate earlier and to a much greater extent than astrocytes, they can divide when in ramified form, and GD3 is up-regulated in most reactive microglia and in a subset of reactive astrocytes. We also conclude that microglial proliferation precedes proliferation of invading blood-borne macrophages.

Animals↗

PubMed1994

B7/BB-1 antigen expression on adult human microglia studied in vitro and in situ.

In this study, we have examined the expression and function of B7/BB-1 on individual glial cells, by utilizing surgically resected adult human central nervous system (CNS) tissues, tissues derived from fetal human CNS, and pathology material from cases of multiple sclerosis (MS). Immunofluorescence analysis using enriched adult human derived cultures of microglia and oligodendrocytes, and mixed microglia/astrocyte cultures, demonstrated that B7/BB-1 was expressed on microglia. Adult human-derived oligodendrocytes and astrocytes, and human fetal astrocytes were B7/BB-1 negative under all culture conditions. Flow cytometry studies demonstrated a low basal level of B7/BB-1 expression on microglia that was up-regulated following incubation with interferon-gamma (IFN-gamma). Co-culture of purified fresh allogeneic CD4+ T cells with microglia for 24 h resulted in clustering of T cells around microglia and microglial B7/BB-1 expression. Preincubation of microglia with an anti BB-1 monoclonal antibody (mAb) prior to microglia: CD4+ T cell co-cultures resulted in partial inhibition of the ability of microglia both to present recall antigen to autologous CD4+ T cells and to present antigen to allogeneic CD4+ T cells in primary mixed lymphocyte reaction (1 degree MLR). The CTLA-4 Ig fusion protein inhibited the ability of microglia to present antigen in both antigen presentation assays to an even greater extent than did the anti BB-1 mAb. The BB-1 antibody also inhibited the ability of microglia to stimulate previously activated T cells in a secondary 2 degrees MLR. In sections of multiple sclerosis brain, B7/BB-1 expression was observed on activated microglia in select parenchymal lesions, and on perivascular cells and infiltrating monocytes. B7/BB-1 immunoreactivity was not found in normal appearing white matter from MS brain or from non-inflammatory brain specimens. Our results indicate that the B7/BB-1 molecule plays a functional role in the capacity of microglia to serve as CNS antigen-presenting cells that can both initiate and perpetuate CD4+ T cell activation.

Abatacept↗

PubMed1995

Human retinal microglia: expression of immune markers and relationship to the glia limitans.

The immunoreactivity, morphology and relationship to the glia limitans of microglia were investigated in flatmounts and sections of normal human retina, using immunogold histochemistry, electron microscopy (EM), and antibodies directed against CD45, major histocompatability complex class I (MHC-I), MHC-II, and human macrophage antigens. Immunoreactivity was evident for all antibodies tested, including MHC-I, which labeled both microglia and retinal vascular endothelium. Most consistent labeling was obtained using antibodies to CD45, MHC-II, and anti-human macrophage (S22) antigen. Immunoreactive cells were seen in the perivascular space (perivascular cells), where they were closely adherent to the vessel profile, and in the retinal parenchyma (microglia). Some parenchymal microglia were also vessel associated and by EM were seen to be closely related to the glia limitans (paravascular microglia). Paravascular microglia were shown by optical densitometry, to express higher levels of MHC antigens than neighboring, non-vessel associated, parenchymal microglia. In addition, paravascular microglia were macrophage (S22) antigen positive, while other parenchymal microglia did not express macrophage antigens. Quantitative data indicate that similar populations of microglia are immunoreactive to CD45, MHC-I, and MHC-II, while relatively few microglia (approximately 10%) are immunoreactive for human macrophage (S22) antigens, supporting previous suggestions that microglia are a heterogeneous population.

Adolescent↗

PubMed2006

Comparative study of microglia activation induced by amyloid-beta and prion peptides: role in neurodegeneration.

The inflammatory responses in Alzheimer's disease (AD) and prion-related encephalopathies (PRE) are dominated by microglia activation. Several studies have reported that the amyloid-beta (Abeta) peptides, which are associated with AD, and the pathogenic isoform of prion protein (PrPSc) have a crucial role in neuronal death and gliosis that occur in both of these disorders. In this study, we investigate whether Abeta and PrPSc cause microglia activation per se and whether these amyloidogenic peptides differentially affect these immunoeffector cells. In addition, we also determined whether substances released by Abeta- and PrP-activated microglia induce neuronal death. Cultures of rat brain microglia cells were treated with the synthetic peptides Abeta1-40, Abeta1-42 and PrP106-126 for different time periods. The lipopolysaccharide was used as a positive control of microglia activation. Our results show that Abeta1-40 and PrP106-126 caused similar morphological changes in microglia and increased the production of nitric oxide and hydroperoxides. An increase on inducible nitric oxide synthase expression was also observed in microglia treated with Abeta1-40 or PrP106. However, these peptides affected in a different manner the secretion of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) secretion. In cocultures of microglia-neurons, it was observed that microglia treated with Abeta1-40 or PrP106-126 induced a comparable extent of neuronal death. The neutralizing antibody for IL-6 significantly reduced the neuronal death induced by Abeta- or PrP-activated microglia. Taken together, the data indicate that Abeta and PrP peptides caused microglia activation and differentially affected cytokine secretion. The IL-6 released by reactive microglia caused neuronal injury.

Amyloid beta-Peptides↗

PubMed1996

Neuron-microglia interactions in vitro.

We observed that soluble factor(s) in microglia-conditioned medium supported the survival of cerebral cortical neurons from E15 mouse in a dose-dependent manner. In mixed neuron-microglia cultures, neurons possessed long neurites with extensive arborization and could survive for up to 4 weeks. In such cultures, neurons had an up-regulated level of phosphotyrosine immunoreactivity as compared to those in pure neuron cultures. In mixed cultures, microglia extended cytoplasmic processes toward the growing neurites, and when they contacted neurites, the microglia changed morphology by flattening and rounding up by extending thin cytoplasmic processes. Microglia survived longer in mixed cultures than in pure microglia cultures, with or without neuron-conditioned medium. Under all these culture conditions, microglia were phagocytic as evaluated by Fc receptor-mediated phagocytosis of opsinized sheep erythrocytes, suggesting that the phagocytic activity of microglia does not impair their capacity to support neuronal survival. However, lipopolysaccharide treated microglia did impede neuronal survival in mixed cultures. These observations indicate that, in vitro, microglia can be either neurotrophic or neurotoxic depending upon the microenvironment. The mixed neuron-microglia cultures described provide a valuable in vitro model systems for studying the direct interactions between neurons and microglia.

Animals↗

PubMed1995

Microglia: intrinsic immuneffector cell of the brain.

Microglia form a regularly spaced network of resident glial cells throughout the central nervous system (CNS). They are morphologically, immunophenotypically and functionally related to cells of the monocyte/macrophage lineage. In the ultimate vicinity of the blood-brain barrier two specialized subsets of macrophages/microglia can be distinguished: firstly, perivascular cells which are enclosed within the basal lamina and secondly juxtavascular microglia which make direct contact with the parenchymal side of the CNS vascular basal lamina but represent true intraparenchymal resident microglia. Bone marrow chimera experiments indicates that a high percentage of the perivascular cells undergoes replacement with bone marrow-derived cells. In contrast, juxtavascular microglia like other resident microglia form a highly stable pool of CNS cells with extremely little turnover with the bone marrow compartment. Both the perivascular cells and the juxtavascular microglia play an important role in initiating and maintaining CNS autoimmune injury due to their strategic localization at a site close to the blood-brain barrier, their rapid inducibility for MHC class II antigens and their potential scavenger role as phagocytic cells. The constantly replaced pool of perivascular cells probably represents an entry route by which HIV gets access to the brain. Microglia are the first cell type to respond to several types of CNS injury. Microglial activation involves a stereotypic pattern of cellular responses, such as proliferation, increased or de-novo expression of immunomolecules, recruitment to the site of injury and functional changes, e.g., the release of cytotoxic and/or inflammatory mediators. In addition, microglia have a strong antigen presenting function and a pronounced cytotoxic function. Microglial activation is a graded response, i.e., microglia only transform into intrinsic brain phagocytes under conditions of neuronal and or synaptic/terminal degeneration. In T-cell-mediated autoimmune injury of the nervous system, microglial activation follows these lines and occurs at an early stage of disease development. In experimental autoimmune encephalomyelitis (EAE), microglia proliferate vigorously, show a strong expression of MHC class I and II antigens, cell adhesion molecules, release of reactive oxygen intermediates and inflammatory cytokines and transform into phagocytic cells. Due to their pronounced antigen presenting function in vitro, activated microglia rather than astrocytes or endothelial cells are the candidates as intrinsic antigen presenting cel of the brain. In contrast to microglia, astrocytes react with a delay, appear to encase morphologically the inflammatory lesion and may be instrumental in downregulating the T-cell-mediated immune injury by inducing T-cell apoptosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain↗

PubMed2006

Microglia provide neuroprotection after ischemia.

Many neurological insults are accompanied by a marked acute inflammatory reaction, involving the activation of microglia. Using a model of exogenous application of fluorescence-labeled BV2 microglia in pathophysiologically relevant concentrations onto organotypic hippocampal slice cultures, we investigated the specific effects of microglia on neuronal damage after ischemic injury. Neuronal cell death after oxygen-glucose deprivation (OGD) was determined by propidium iodide incorporation and Nissl staining. Migration and interaction with neurons were analyzed by time resolved 3-D two-photon microscopy. We show that microglia protect against OGD-induced neuronal damage and engage in close physical cell-cell contact with neurons in the damaged brain area. Neuroprotection and migration of microglia were not seen with integrin regulator CD11a-deficient microglia or HL-60 granulocytes. The induction of migration and neuron-microglia interaction deep inside the slice was markedly increased under OGD conditions. Lipopolysaccharide-prestimulated microglia failed to provide neuroprotection after OGD. Pharmacological interference with microglia function resulted in a reduced neuroprotection. Microglia proved to be neuroprotective even when applied up to 4 h after OGD, thus defining a "protective time window." In acute injury such as trauma or stroke, appropriately activated microglia may primarily have a neuroprotective role. Anti-inflammatory treatment within the protective time window of microglia would therefore be counterintuitive.

Animals↗

PubMed2004

Ultrastructural evaluation of activated forms of microglia in human brain in selected neurological diseases (SSPE, Wilson's disease and Alzheimer's disease).

Activated forms of microglia were ultrastructurally evaluated in three neurological diseases of different aetiology (subacute sclerosing panencephalitis--SSPE, Wilson's disease and Alzheimer's disease). The occurrence of activated rod, ramified and amoeboid microglia was found in the investigated diseases. The widest ultrastructural variability of microglia was in SSPE, including the presence of mitotic chromosomes or centrioles in its cytoplasm, which indicates microglia proliferation. In the nuclei of activated microglia, some nuclear bodies with different structures were frequently seen, whereas lamellar structures (similar to developing Birbeck's bodies--pathognomonic to Langerhans-type dendritic cells) were observed in the cytoplasm. The activated forms of microglia with apoptotic features were found only in SSPE cases. Some apoptotic nuclei were filled with nucleocapsids of measles virus. In Alzheimer's disease, activated microglia was most frequently bound to senile plaques. Ramified microglia was in contact with amyloid fibrils, which penetrated its cytoplasm and reached the nuclear membrane and channels of rough endoplasmic reticulum, or was situated among dystrophic neurites. Rod microglia was found predominantly at the edge of senile plaques. In Wilson's disease, the ultrastructure of activated microglia showed mostly indirect forms between rod, ramified and amoeboid microglia. The microglia ultrastructure suggests that its morphological form may express functional involvement in the pathogenesis of a given disease entity.

Adolescent↗

PubMed1996

Microglia in human retina: a heterogeneous population with distinct ontogenies.

Microglia of the adult human retina are a heterogeneous population of cells, some having characteristics of dendritic antigen presenting cells (DC) and others resembling macrophages, or MPS cells. Studies of the development of microglial distributions in human retina suggest that cells bearing macrophage markers are ontogenetically distinct from microglia that do not. Quantitative studies indicate that macrophage antigen immunoreactive microglia are a subpopulation CD45- and MHC-immunoreactive microglia. While CD45 and MHC-I and -II immunoreactive microglia are seen in the retina prior to the arrival of the vasculature, significant numbers of macrophage-positive microglia only arrive along with the vascular precursors, at about 14 to 15 weeks of gestation. Microglia appear to enter the retina from the ciliary margin prior to vascularization but from both the optic disc and ciliary margin, postvascularization. Macrophage antigen positive microglia enter the retina mainly via the optic nerve head. It is argued that macrophage-antigen positive microglia become established in the retina as vessel associated (perivascular and paravascular) microglia and that the MHC-positive, but macrophage-antigen negative microglia (representing DC), become established as the parenchymal, ramified microglia of adult retina.

Adult↗

PubMed1998

Properties of activated microglia and pharmacologic interference by propentofylline.

Ameboid microglia are activated macrophages in the developing brain. With age, these cells undergo gradual transformation into the adult form, known as ramified or resting microglia. In response to neuronal insults, microglia change their morphology and immunophenotype and proliferate to become full-blown brain macrophages. Microglia release a battery of neurotoxic substances. Responses to neuronal damage occur at various intervals after the insult, suggesting that microglia may be an attractive target for pharmacologic intervention. The cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients contains antibodies that recognize activated microglia in the developing rat and in the ischemic gerbil brain. These results suggest that AD shares common mechanisms related to the activation of microglia with both these experimental models. In vitro, the xanthine derivative propentofylline (PPF) depresses the production of reactive oxygen intermediates produced by macrophages. To appreciate in vivo interactions of PPF, two models were employed: developing rats and adult gerbils exposed to ischemia. Newborn rats were administered PPF (10 mg/kg) for 7 days. Gerbils were exposed to 5 min of transient forebrain ischemia and received PPF (10 mg/kg) 24 h later until the day before sacrifice. Animals were sacrificed at 7 or 14 days after reperfusion. Brains were processed for immunocytochemistry. Reactive microglia were visualized with monoclonal antibodies OX18 and OX42 or AD-CSF microglia antibodies. In the case of ischemia, an antibody against the amyloid precursor protein (APP) (residues 676-695) was included. Newborn rats receiving PPF for 7 days displayed a dramatic reduction in the number of activated microglia compared with untreated littermates. Ischemic control in gerbils showed complete nerve death, accumulations of APP, and enhanced microglial reactivity. In gerbils receiving PPF, APP accumulation was absent or very slight, and activated microglia were downregulated. The ability of PPF to interfere with activated microglia suggests that this agent may be useful for slowing progressive nerve cell death associated with AD, which is considered to be largely influenced by pathologic glial reactions.

Adult↗

PubMed1998

Mature microglia resemble immature antigen-presenting cells.

Owing to the difficulties of isolating adequate numbers of microglia from adult tissue, much of our understanding of their function is based on characterizations of microglia that develop in mixed glial cultures. To learn more about the nature of these cells in vivo, we have compared the phenotypes of murine microglia isolated from adults, neonates, and from mixed glial cultures with spleen cells from fetuses, neonates, and adults. In the adult CNS, the only resident population of cells that express CD45, a protein tyrosine phosphatase, are the F4/80+ and FcR+ cells: the microglia. In contrast to all other differentiated cells of hemopoietic origin, microglial CD45 levels fail to increase from the neonatal period through adulthood. Rather, their levels are indistinguishable from the low levels found on a small population of embryonic day 16 liver cells. Conversely, we find that the F4/80 values of microglia are elevated as compared to splenic macrophages. Strikingly, microglia that develop in mixed glial cultures display a more activated phenotype, with low F4/80 values, weak MHC class II expression, and the appearance of a subset of cells positive for the dendritic cell marker, NLDC145. Additionally, CD45 values are elevated to a level intermediate between that of adult microglia and adult spleen, a level similar to that found on microglia activated in vivo. Consistent with this activated phenotype, indomethacin revealed the ability of mixed glial culture microglia to present a peptide antigen to naive T-cells expressing a defined T-cell receptor. Although adult microglia did express costimulatory molecules, B7.2, ICAM-1, and CD40, and could be induced to express MHC class II, they failed to present antigen in the same assay. Interestingly, these same cells could stimulate T-cell proliferation in a mixed lymphocyte reaction but not in an allogeneic specific manner. Taken together these data suggest that adult microglia remain in a relatively immature and unactivated state of differentiation as compared to other tissue macrophages.

Animals↗

PubMed2005

Interactive role of the toll-like receptor 4 and reactive oxygen species in LPS-induced microglia activation.

Microglia are activated by lipopolysaccharide (LPS) to produce neurotoxic pro-inflammatory factors and reactive oxygen species (ROS). While a multitude of LPS receptors and corresponding pathways have been identified, the detailed mechanisms mediating the microglial response to LPS are unclear. Using mice lacking a functional toll-like receptor 4 (TLR4), we demonstrate that TLR4 and ROS work in concert to mediate microglia activation, where the contribution from each pathway is dependent on the concentration of LPS. Immunocytochemical staining of microglia in neuron-glia cultures with antibodies against F4/80 revealed that while TLR4(+/+) microglia were activated the low concentration of 1 ng/ml of LPS, TLR4(-/-) microglia exhibit activated morphology in response to LPS only at higher concentrations (100-1,000 ng/ml). Additionally, tumor necrosis factor-alpha (TNF-alpha) was only produced from higher concentrations (100-1,000 ng/ml) of LPS in TLR4(-/-) enriched microglia cultures. Diphenylene iodonium (DPI), an inhibitor of NADPH oxidase, reduced TNF-alpha production from TLR4(-/-) microglia. The influence of TLR4 on LPS-induced superoxide production was tested in rat enriched microglia cultures, where the presence or absence of serum failed to show any effect on the superoxide production. Further, both TLR4(-/-) and TLR4(+/+) microglia showed a similar increase in extracellular superoxide production when exposed to LPS (1-1,000 ng/ml). These data indicate that LPS-induced superoxide production in microglia is independent of TLR4 and that ROS derived from the production of extracellular superoxide in microglia mediates the LPS-induced TNF-alpha response of both the TLR4-dependent and independent pathway.

Animals↗

PubMed2006

Pathological dynamics of activated microglia following medial forebrain bundle transection.

To elucidate the role and pathological dynamics of activated microglia, this study assessed the phagocytic, immunophenotypic, morphological, and migratory properties of activated microglia in the medial forebrain bundle (MFB) axotomized rat brain. Activated microglia were identified using two different monoclonal antibodies: ED1 for phagocytic activity and OX6 for major histocompatibility complex (MHC) class II. Phagocytic microglia, characterized by ED1-immunoreactivity or ED1- and OX6-immunoreactivity, appeared in the MFB and substantia nigra (SN) as early as 1-3 days post-lesion (dpl), when there was no apparent loss of SN dopamine (DA) neurons. Thereafter, a great number of activated microglia selectively adhered to degenerating axons, dendrites and DA neuronal somas of the SN. This was followed by significant loss of these fibers and nigral DA neurons. Activation of microglia into phagocytic stage was most pronounced between 14 approximately 28 dpl and gradually subsided, but phagocytic microglia persisted until 70 dpl, the last time point examined. ED1 expression preceded MHC II expression in phagocytic microglia. All phagocytic microglia sticking to DA neurons showed activated but ramified form with enlarged somas and thickened processes. They were recruited to the SNc from cranial, dorsal and ventral aspects along various structures and finally stuck to DA neurons of the SNc. Characteristic rod-shaped microglia in the white matter were thought to migrate a long distance. The present study strongly suggests that neurons undergoing delayed neurodegeneration may be phagocytosed by numerous phagocytic, ramified microglia at various sites where specific surface signals are exposed or diffusible molecules are released.

Animals↗

PubMed2001

Microglia in neuroregeneration.

Microglia has the potential to produce and release a range of factors that directly and/or indirectly promote regeneration in the injured nervous system. The overwhelming evidence indicates, however, that this potential is generally not expressed in vivo. Activated microglia may enhance neuronal degeneration following axotomy, thereby counteracting functional recovery. Microglia does not seem to contribute significantly to axonal outgrowth after peripheral nerve injury, since this process proceeds uneventful even if perineuronal microglia is eliminated. The phagocytic phenotype of microglia is highly suppressed during Wallerian degeneration in the central nervous system. Therefore, microglia is incapable of rapid and efficient removal of myelin debris and its putative growth inhibitory components. In this way, microglia may contribute to regeneration failure in the central nervous system. Structural and temporal correlations are compatible with participation by perineuronal microglia in axotomy-induced shedding of presynaptic terminals, but direct evidence for such participation is lacking. Currently, the most promising case for a promoting effect on neural repair by activated microglia appears to be as a mediator of collateral sprouting, at least in certain brain areas. However, final proof for a critical role of microglia in these instances is still lacking. Results from in vitro studies demonstrate that microglia can develop a regeneration supportive phenotype. Altering the microglial involvement following neural injury from a typically passive or even counterproductive state and into a condition where these cells are actively supporting regeneration and plasticity is, therefore, an exciting challenge and probably a realistic goal.

Central Nervous System↗