SEARCH · PubMed Health

Results for “Microglia”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources

PubMed2004

Role of microglia in central nervous system infections.

The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed.

Animals↗

PubMed2001

In vitro investigation of host resistance to Toxoplasma gondii infection in microglia of BALB/c and CBA/Ca mice.

Toxoplasmic encephalitis (TE) is a life-threatening disease of immunocompromised individuals and has increased in prevalence as a consequence of AIDS. TE has been modeled in inbred mice, with CBA/Ca mice being susceptible and BALB/c mice resistant to the development of TE. To better understand the innate mechanisms in the brain that play a role in resistance to TE, nitric oxide (NO)-dependent and NO-independent mechanisms were examined in microglia from BALB/c and CBA/Ca mice and correlated with the ability of these cells to inhibit Toxoplasma gondii replication. These parameters were measured 48 h after stimulation with lipopolysaccharide (LPS) gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), or combinations of these inducers in T. gondii-infected microglia isolated from newborn mice. CBA/Ca microglia consistently produced less NO than did BALB/c microglia after stimulation with LPS or with IFN-gamma plus TNF-alpha, and they inhibited T. gondii replication significantly less than did BALB/c microglia. Cells of both strains treated with IFN-gamma alone significantly inhibited uracil incorporation by T. gondii, and N(G)-monomethyl-L-arginine (NMMA) treatment did not reverse this effect. In cells treated with IFN-gamma in combination with other inducers, NMMA treatment resulted in only partial recovery of T. gondii replication. This IFN-gamma-dependent inhibition of replication was not due to generation of reactive oxygen species or to increased tryptophan degradation. These data suggest that NO production and an IFN-gamma-dependent mechanism contribute to the inhibition of T. gondii replication after in vitro stimulation with IFN-gamma plus TNF-alpha or with LPS. Differences in NO production but not in IFN-gamma-dependent inhibition of T. gondii replication were observed between CBA/Ca and BALB/c microglia.

Animals↗

PubMed2001

Cryptococcus neoformans induces macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta in human microglia: role of specific antibody and soluble capsular polysaccharide.

We characterized the expression of the beta-chemokines macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES by primary human microglia after exposure to Cryptococcus neoformans. In the absence of specific antibody, C. neoformans failed to elicit a chemokine response, while in the presence of specific antibody, microglia produced MIP-1alpha and MIP-1beta in amounts comparable to those induced by lipopolysaccharide. RANTES was also induced but at much lower levels. In addition to MIP-1alpha and MIP-1beta mRNA, we observed a robust induction of monocyte chemoattractant protein 1 and interleukin-8 mRNA following incubation of microglia with opsonized C. neoformans. In contrast, cryptococcal polysaccharide did not induce a chemokine response even when specific antibody was present and inhibited the MIP-1alpha induction associated with antibody-mediated phagocytosis of C. neoformans. The role of the Fc receptor in the observed chemokine induction was explored in several experiments. Treatment of microglia with cytochalasin D inhibited internalization of C. neoformans but did not affect MIP-1alpha induction. In contrast, treatment with herbimycin A, a tyrosine kinase inhibitor, inhibited MIP-1alpha induction. Microglia stimulated with immobilized murine immunoglobulin also produced MIP-1alpha and RANTES (MIP-1alpha > RANTES). Our results show that microglia produce several chemokines when stimulated by C. neoformans in the presence of specific antibody and that this process is likely to be mediated by Fc receptor activation. This response can be down-regulated by cryptococcal capsular polysaccharide. These findings suggest a mechanism by which C. neoformans infections fail to induce strong inflammatory responses in patients with cryptococcal meningoencephalitis and have important implications for antibody therapy.

Antibodies, Fungal↗

PubMed2002

Fcgamma receptor I- and III-mediated macrophage inflammatory protein 1alpha induction in primary human and murine microglia.

Microglial cell phagocytic receptors may play important roles in the pathogenesis and treatment of several neurological diseases. We studied microglial Fc receptor (FcR) activation with respect to the specific FcgammaR types involved and the downstream signaling events by using monoclonal antibody (MAb)-coated Cryptococcus neoformans immune complexes as the stimuli and macrophage inflammatory protein 1alpha (MIP-1alpha) production as the final outcome. C. neoformans complexed with murine immunoglobulin G (IgG) of gamma1, gamma2a, and gamma3, but not gamma2b isotype, was effective in inducing MIP-1alpha in human microglia. Since murine gamma2b binds to human FcgammaRII (but not FcgammaRI or FcgammaRIII), these results indicate that FcgammaRI and/or FcgammaRIII is involved in MIP-1alpha production. Consistent with this, an antibody that blocks FcgammaRII (IV.3) failed to inhibit MIP-1alpha production, while an antibody that blocks FcgammaRIII (3G8) did. An anti-C. neoformans MAb, 18B7 (IgG1), but not its F(ab')(2), induced extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase kinase phosphorylation, and MIP-1alpha release was suppressed by the ERK inhibitor U0126. C. neoformans plus 18B7 also induced degradation of I-kappaBalpha, and MIP-1alpha release was suppressed by the antioxidant NF-kappaB inhibitor pyrrolidine dithiocarbamate. To confirm the role of FcR more directly, we isolated microglia from wild-type and various FcR-deficient mice and then challenged them with C. neoformans plus 18B7. While FcgammaRII-deficient microglia showed little difference from the wild-type microglia, both FcgammaRI alpha-chain- and FcgammaRIII alpha-chain-deficient microglia produced less MIP-1alpha, and the common Fc gamma-chain-deficient microglia showed no MIP-1alpha release. Taken together, our results demonstrate a definitive role for FcgammaRI and FcgammaRIII in microglial chemokine induction and implicate ERK and NF-kappaB as the signaling components leading to MIP-1alpha expression. Our results delineate a new mechanism for microglial activation and may have implications for central nervous system inflammatory diseases.

Animals↗

PubMed2003

Soluble factors released by Toxoplasma gondii-infected astrocytes down-modulate nitric oxide production by gamma interferon-activated microglia and prevent neuronal degeneration.

The maintenance of a benign chronic Toxoplasma gondii infection is mainly dependent on the persistent presence of gamma interferon (IFN-gamma) in the central nervous system (CNS). However, IFN-gamma-activated microglia are paradoxically involved in parasitism control and in tissue damage during a broad range of CNS pathologies. In this way, nitric oxide (NO), the main toxic metabolite produced by IFN-gamma-activated microglia, may cause neuronal injury during T. gondii infection. Despite the potential NO toxicity, neurodegeneration is not a common finding during chronic T. gondii infection. In this work, we describe a significant down-modulation of NO production by IFN-gamma-activated microglia in the presence of conditioned medium of T. gondii-infected astrocytes (CMi). The inhibition of NO production was paralleled with recovery of neurite outgrowth when neurons were cocultured with IFN-gamma-activated microglia in the presence of CMi. Moreover, the modulation of NO secretion and the neuroprotective effect were shown to be dependent on prostaglandin E(2) (PGE(2)) production by T. gondii-infected astrocytes and autocrine secretion of interleukin-10 (IL-10) by microglia. These events were partially eliminated when infected astrocytes were treated with aspirin and cocultures were treated with anti-IL-10 neutralizing antibodies and RP-8-Br cyclic AMP (cAMP), a protein kinase A inhibitor. Further, the modulatory effects of CMi were mimicked by the presence of exogenous PGE(2) and by forskolin, an adenylate cyclase activator. Altogether, these data point to a T. gondii-triggered regulatory mechanism involving PGE(2) secretion by astrocytes and cAMP-dependent IL-10 secretion by microglia. This may reduce host tissue inflammation, thus avoiding neuron damage during an established Th1 protective immune response.

Animals↗

PubMed2001

Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler's virus.

Microglia are resident central nervous system (CNS) macrophages. Theiler's murine encephalomyelitis virus (TMEV) infection of SJL/J mice causes persistent infection of CNS microglia, leading to the development of a chronic-progressive CD4(+) T-cell-mediated autoimmune demyelinating disease. We asked if TMEV infection of microglia activates their innate immune functions and/or activates their ability to serve as antigen-presenting cells for activation of T-cell responses to virus and endogenous myelin epitopes. The results indicate that microglia lines can be persistently infected with TMEV and that infection significantly upregulates the expression of cytokines involved in innate immunity (tumor necrosis factor alpha, interleukin-6 [IL-6], IL-18, and, most importantly, type I interferons) along with upregulation of major histocompatibility complex class II, IL-12, and various costimulatory molecules (B7-1, B7-2, CD40, and ICAM-1). Most significantly, TMEV-infected microglia were able to efficiently process and present both endogenous virus epitopes and exogenous myelin epitopes to inflammatory CD4(+) Th1 cells. Thus, TMEV infection of microglia activates these cells to initiate an innate immune response which may lead to the activation of naive and memory virus- and myelin-specific adaptive immune responses within the CNS.

Animals↗

PubMed2005

Rabies virus-induced activation of mitogen-activated protein kinase and NF-kappaB signaling pathways regulates expression of CXC and CC chemokine ligands in microglia.

Following virus infection of the central nervous system, microglia, the ontogenetic and functional equivalents of macrophages in somatic tissues, act as sources of chemokines, thereby recruiting peripheral leukocytes into the brain parenchyma. In the present study, we have systemically examined the growth characteristics of rabies virus (RV) in microglia and the activation of cellular signaling pathways leading to chemokine expression upon RV infection. In RV-inoculated microglia, the synthesis of the viral genome and the production of virus progenies were significantly impaired, while the expression of viral proteins was observed. Transcriptional analyses of the expression profiles of chemokine genes revealed that RV infection, but not exposure to inactivated virions, strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. RV infection triggered the activation of signaling pathways mediated by mitogen-activated protein kinases, including p38, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase, and nuclear factor kappaB (NF-kappaB). RV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-kappaB pathways. In contrast, the activation of ERK1/2 was found to down-regulate CCL5 expression in RV-infected microglia, despite the fact that it was involved in partial induction of CXCL10 expression. Furthermore, NF-kappaB signaling upon RV infection was augmented via a p38-mediated mechanism. Taken together, these results indicate that the strong induction of CXCL10 and CCL5 expression in microglia is precisely regulated by the activation of multiple signaling pathways through the recognition of RV infection.

Animals↗

PubMed1998

Ion channels in microglia (brain macrophages).

Microglia are immunocompetent cells in the brain that have many similarities with macrophages of peripheral tissues. In normal adult brain, microglial cells are in a resting state, but they become activated during inflammation of the central nervous system, after neuronal injury, and in several neurological diseases. Patch-clamp studies of microglial cells in cell culture and in tissue slices demonstrate that microglia express a wide variety of ion channels. Six different types of K+ channels have been identified in microglia, namely, inward rectifier, delayed rectifier, HERG-like, G protein-activated, as well as voltage-dependent and voltage-independent Ca2+-activated K+ channels. Moreover, microglia express H+ channels, Na+ channels, voltage-gated Ca2+ channels, Ca2+-release activated Ca2+ channels, and voltage-dependent and voltage-independent Cl- channels. With respect to their kinetic and pharmacological properties, most microglial ion channels closely resemble ion channels characterized in other macrophage preparations. Expression patterns of ion channels in microglia depend on the functional state of the cells. Microglial ion channels can be modulated by exposure to lipopolysaccharide or various cytokines, by activation of protein kinase C or G proteins, by factors released from astrocytes, by changes in the concentration of internal free Ca2+, and by variations of the internal or external pH. There is evidence suggesting that ion channels in microglia are involved in maintaining the membrane potential and are also involved in proliferation, ramification, and the respiratory burst. Further possible functional roles of microglial ion channels are discussed.

Adult↗

PubMed2006

Microglia activation in the brain as inflammatory biomarker of Alzheimer's disease neuropathology and clinical dementia.

The role of microglia-mediated inflammation in the progression of Alzheimer's disease (AD) neuropathology remains unclear. In this study, postmortem brain sections from AD and control cases were subjected to Human Leukocyte Antigen (HLA)-DR immunohistochemistry to examine microglia activation in the progression of AD assessed by pre-mortem clinical dementia rating (CDR) and postmortem pathological manifestations of neuritic plaque (NP) and neurofibrillary tangle (NT) according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). In both gray and white matter of the entorhinal cortex (EC) and HLA-DR immunostaining increased with the progression of CDR or CERAD NP, and to a lesser degree with CERAD NT. Between CDR stages HLA-DR significance was found in moderate (CDR 2) to severe dementia (CDR 5) where as between CERAD NP stages staining increased significantly from NP 0 (no plaque) to NP 1 (sparse plaques), suggesting increased microglia activation begins with amyloid NP deposition. In the hippocampus, a significant increase in microglia immunostaining was found in the pyramidal cell layer of CA1 as early as CDR 1, and in the upper molecular layer of the dentate gyrus in CDR 0.5. This increase continues with the progression of CDR and reaches maximum in CDR 5. When assessed by CERAD NP stages however, a significant increase in microglia immunostaining was found only in mid-to-late stages (NP 3) and reduced staining was seen in NP 5. These results suggest that microglia activation increases with the progression of AD, with the increase varying depending on the involved brain region.

Aged↗

PubMed1997

Phagocytic response in photochemically induced infarction of rat cerebral cortex. The role of resident microglia.

BACKGROUND AND PURPOSE: In this study we assessed the relative extent to which resident microglia and blood-borne macrophages contribute to the population of phagocytes after focal infarction of the rat cortex. METHODS: Focal cerebral infarction was induced in rats by photothrombosis after hematogenous macrophages were depleted by means of liposomes containing dichloromethylene diphosphonate. The phagocytic activation of microglia and macrophages was monitored by immunocytochemistry with the antibody ED1. RESULTS: In both macrophage-depleted rats and controls, ED1+ phagocytes bordered the infarct to the same extent at day 3 after photothrombosis. By contrast, at day 6 after photothrombosis ED1+ phagocytes in control rats greatly outnumbered those in macrophage-depleted rats. With the use of the antibody Ox42 directed against the CR3 receptor on the surface of microglia, it was possible to selectively document the transition of resident microglia into stellate and ameboid phagocytic microglia during the first 6 days after photothrombosis in the absence of bloodborne macrophages. CONCLUSIONS: The initial phagocytic response after focal brain ischemia is an intrinsic property of the nervous system mainly performed by resident microglia. The majority of hematogenous macrophages are recruited secondarily to participate in the removal of necrotic tissue.

Animals↗

PubMed2003

Pathogenic role of retinal microglia in experimental uveoretinitis.

PURPOSE: To devise methods for unequivocal identification of activated retinal microglia in experimental autoimmune uveoretinitis (EAU) and to investigate their role in the development of EAU. METHODS: A group of Lewis rats underwent optic nerve axotomy with the application of N-4-(4-didecylaminostyryl)-N methylpyridinium iodide (4Di-10ASP) at the axotomy site. On days 3, 14, and 38 after axotomy, the rats were killed, the eyes were enucleated, and the retinas were stained for OX42. Another group of such axotomized rats were immunized with S-antigen peptide and were killed on days 7 through 12 after the injection with peptide. The enucleated eyes were stained for OX42 and examined by confocal microscope. After axotomy, bone marrow (Y-->X) chimeric rats were injected with S-antigen peptide and were killed on days 10 and 12 after injection. The retinas were evaluated by PCR with Y-specific primers. Finally, a group of axotomized rats was injected with the S-antigen peptide and killed on days 6, 8, 9, and 10 after injection. Their enucleated eyes were examined for microglial expression of TNFalpha and for generation of peroxynitrite. RESULTS: In the axotomized, non-EAU eyes, 4Di-10ASP-labeled ganglion cells were detectable on days 3 and 14, and 4Di-10ASP-containing OX42-positive cells (microglia) were found in the nerve fiber and other inner retinal layers on days 14 and 38. The S-antigen peptide-injected rats showed migration of the microglia (4Di-10ASP-positive and OX42-positive) to the photoreceptor cell layer on day 9, and these cells increased in number at this site on day 10. No macrophages (OX42-positive and 4Di-10ASP-negative) were present at this early stage of EAU, but such cells appeared in the retina on days 11 and 12. PCR of the chimeric EAU retinas showed an absence of the Y chromosome-amplified product on day 10, but the presence of this product was detected on day 12. The expression of TNFalpha and generation of peroxynitrite were noted in the migrated microglia at the photoreceptor cell layer on days 9 and 10 of EAU. CONCLUSIONS: In the early phase of EAU, the microglia migrate to the photoreceptor cell layer where they generate TNFalpha and peroxynitrite. Such microglial migration and activation take place before infiltration of the macrophages. These findings indicate a novel pathogenic mechanism of EAU, in which retinal microglia may initiate retinitis with subsequent recruitment of circulation-derived phagocytes, leading to the amplification of uveoretinitis.

Animals↗

PubMedDate not supplied

P2Y1 and cysteinyl leukotriene receptors mediate purine and cysteinyl leukotriene co-release in primary cultures of rat microglia.

Inflammation is widely recognized as contributing to the pathology of acute and chronic neurodegenerative conditions. Microglial cells are pathologic sensors in the brain and activated microglia have been viewed as detrimental. Leukotriene, including cysteinyl leukotrienes (CysLTs) are suggested to be involved in brain inflammation and neurological diseases and ATP, by its receptors is a candidate for microglia activation. A23187 (10 microM) stimulated microglia to co-release CysLTs and [3H] adenine based purines ([3H] ABPs), mainly ATP. The biosynthetic production of CysLTs was abolished by 10 microM MK-886, an inhibitor of 5-lipoxygenase-activating protein activity. RT-PCR analysis showed that microglia expressed both CysLT1 / CysLT2 receptors, P2Y1ATP receptors and several members of the ATP binding cassette (ABC) transporters including MRP1, MRP4 and Pgp. The increase in [Ca2+]i elicited by LTD4 (0.1 microM) and 2MeSATP (100 microM), agonists for CysLT- and P2Y1-receptors, was abolished by the respective antagonists, BAYu9773 (0.5 microM) and suramin (50 microM). The stimulation of both receptor subtypes, induced a concomitant increase in the release of both [3H] ABPs and CysLTs that was blocked by the antagonists and significantly reduced by a cocktail of ABC transporter inhibitors, BAPTA/AM (intracellular Ca2+ chelator) and staurosporine (0.1 microM, PKC blocker). P2Y antagonist was unable to antagonise the effects of LTD4 and BAYu9773 did not reduce the effects of 2MeSATP. These data suggest that: i) the efflux of purines and cysteinyl-leukotrienes is specifically and independently controlled by the two receptor types, ii) calcium, PKC and the ABC transporter system can reasonably be considered common mechanisms underlying the release of ABPs and CysLTs from microglia. The blockade of P2Y1 or CysLT1/CysLT2 receptors by specific antagonists that abolished the raise in [Ca2+]i and drastically reduced the concomitant efflux of both compounds, as well as the effects of BAPTA and staurosporine support this hypothesis. In conclusion, the data of the present study suggest a cross talk between the purine and leukotriene systems in a possible autocrine/paracrine control of the microglia-mediated initiation and progression of an inflammatory response.

ATP-Binding Cassette Transporters↗

PubMed2001

Effect of a short-term in vitro exposure to the marine toxin domoic acid on viability, tumor necrosis factor-alpha, matrix metalloproteinase-9 and superoxide anion release by rat neonatal microglia.

BACKGROUND: The excitatory amino acid domoic acid, a glutamate and kainic acid analog, is the causative agent of amnesic shellfish poisoning in humans. No studies to our knowledge have investigated the potential contribution to short-term neurotoxicity of the brain microglia, a cell type that constitutes circa 10% of the total glial population in the brain. We tested the hypothesis that a short-term in vitro exposure to domoic acid, might lead to the activation of rat neonatal microglia and the concomitant release of the putative neurotoxic mediators tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinases-2 and-9 (MMP-2 and -9) and superoxide anion (O2-). RESULTS: In vitro, domoic acid [10 microM-1 mM] was significantly neurotoxic to primary cerebellar granule neurons. Although neonatal rat microglia expressed ionotropic glutamate GluR4 receptors, exposure during 6 hours to domoic acid [10 microM-1 mM] had no significant effect on viability. By four hours, LPS (10 ng/mL) stimulated an increase in TNF-alpha mRNA and a 2,233 % increase in TNF-alpha protein In contrast, domoic acid (1 mM) induced a slight rise in TNF-alpha expression and a 53 % increase (p < 0.01) of immunoreactive TNF-alpha protein. Furthermore, though less potent than LPS, a 4-hour treatment with domoic acid (1 mM) yielded a 757% (p < 0.01) increase in MMP-9 release, but had no effect on MMP-2. Finally, while PMA (phorbol 12-myristate 13-acetate) stimulated O2- generation was elevated in 6 hour LPS-primed microglia, a similar pretreatment with domoic acid (1 mM) did not prime O2- release. CONCLUSIONS: To our knowledge this is the first experimental evidence that domoic acid, at in vitro concentrations that are toxic to neuronal cells, can trigger a release of statistically significant amounts of TNF-alpha and MMP-9 by brain microglia. These observations are of considerable pathophysiological significance because domoic acid activates rat microglia several days after in vivo administration.

Animals↗

PubMed2024

Analysis of different expression RNA binding protein genes in mouse microglia cell from the brains of mice 72 h after subarachnoid hemorrhage or sham operation.

BACKGROUND: The prognosis of brain injury caused by subarachnoid hemorrhage (SAH) is poor. Previous studies showed that abnormal function of RBPs might be involved in brain injury, neuroinflammation and further affect microglia homeostasis. However, no studies have systematically analyzed the genome-wide abnormal expression of RBPs genes in microglia during SAH. METHODS: RNA-seq data of microglia from the SAH mouse group (SAH) and control sham-operated mouse group (sham) were downloaded from the GEO database in GSE167957, including four samples from the sham group and four samples from the SAH group for subsequent analysis.Utilizing GO and KEGG functional enrichment analyses, we conducted a comprehensive study of differentially expressed genes (DEGs), alternative splicing patterns, and co-expression networks to gain deeper insights into the differential expression of RNA-binding proteins (RBPs) and differential alternative splicing events (ASEs) between the SAH (subarachnoid hemorrhage) and sham groups. This analysis aimed to elucidate the potential mechanisms underlying the aberrant expression of RBPs in microglia during brain injury caused by SAH. RESULTS: ASEs and co-expression analyses of differentially expressed RBPs and differential ASEs were carried out in microglia in terms of gene expression. GO and KEGG functional enrichment analysis showed that aberrantly expressed RBPs such as Mcm7, Mtdh, SRSF3, and Hnrnpa2b1 may affect and regulate downstream Csnk1d, Uckl1 and other protein phosphorylation-related genes by alterative splicing. CONCLUSION: RBPs were aberrantly expressed in microglia during the development of brain injury secondary to SAH, regulating alterative splicing of downstream genes and influencing the progression of SAH brain injury in this study. This implies that RBPs are important for the identification of new therapeutic targets for brain injury after SAH.

Animals↗

PubMed2003

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the production of inflammatory mediators by activated microglia.

Microglia play a central role in the regulation of immune and inflammatory activities, as well as tissue remodeling in the central nervous system. However, activation of microglia is a histopathological hallmark of several neurodegenerative diseases. Pathological microglial activation is believed to contribute to progressive damage in neurodegenerative diseases through the release of proinflammatory and/or cytotoxic factors, including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-12, and nitric oxide (NO). Hence, it is important to unravel mechanisms regulating microglia activation of inflamed brain parenchyma to provide insights into efficient therapeutic intervention. This study examines the role of two anti-inflammatory neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP) on the production of various proinflammatory factors by endotoxin-stimulated microglia. VIP and PACAP inhibit TNF-alpha, IL-1beta, IL-6, and NO production by lipopolysaccharide (LPS)-activated microglia. The specific type 1 VIP receptor mediates the inhibitory effect of VIP/PACAP, and cyclic adenosine monophosphate is the major, second messenger involved. VIP and PACAP regulate the production of these proinflammatory factors at a transcriptional level by inhibiting p65 nuclear translocation and nuclear factor-kappaB-DNA binding. This effect is mediated, as neuropeptides stabilize the inhibitor IkappaB by inhibiting LPS-induced IkappaB-kinase activity. Therefore, the inhibitory effects on the production of proinflammatory mediators define VIP and PACAP as "microglia-deactivating factors" with significant, therapeutical potential for inflammatory/degenerative brain disorders.

Animals↗

PubMed2004

[NO-induced apoptosis and ER stress in microglia].

Nitric Oxide (NO) produced by activated microglia is an important contributor to neuronal damage. NO toxicity is generally thought to be mediated by the DNA damage-p53 pathway or mitochondrial dysfunction. We investigated the mechanism of NO toxicity by using microglial MG5 cells established from p53-deficient mouse. When MG5 cells were exposed to LPS plus IFN-gamma, mRNA and protein for inducible NO synthase (iNOS) were markedly induced and apoptosis occurred. Under these conditions, we found that mRNA and protein for CHOP/GADD153, a C/EBP family transcription factor that is involved in ER stress-induced apoptosis, were induced. These results suggest that NO-induced apoptosis in MG5 cells occurs through the ER stress pathway involving CHOP, but is independent of p53. Overactivation-induced apoptosis may be an essential self-regulatory mechanism for microglia in order to limit bystander killing of vulnerable neurons. On the other hand, recent reports suggest that there may exist two subtypes of microglia at least in the CNS. We found activated rat type-1 microglia induced expression of iNOS and exhibited neurotoxic to rat hippocampal neurons. By contrast, activated type-2 microglia hardly exhibited neurotoxicity in this co-culture system. These results suggest that the two subtype(s) of microglia may regulate differently the inflammatory response in the CNS.

Animals↗

PubMed2004

Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia.

After a brain insult, ATP is released from injured cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor necrosis factor (TNF). The release of TNF appears to be dependent on the P2X7 receptor. The inhibitors 1,4-diamino-2,3-dicyano-1,4-bis[2-amino-phenylthio]butadiene (U0126), anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), and 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)IH-imidazole (SB203580), which target MEK (mitogen-activated protein kinase kinase), JNK (c-Jun N-terminal kinase), and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA is strongly inhibited by U0126 and SP600125. SB203580 did not affect the increased levels of TNF mRNA but did prevent TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38 [but not extracellular signal-regulated kinase (ERK)] could be inhibited by brilliant blue G, a P2X7 receptor blocker, and by genistein and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, which are general and src-family-specific tyrosine kinase inhibitors, respectively. Most important, we found that treatment of the microglia in neuron-microglia cocultures with the P2X7 agonist 2'-3'-O-(benzoyl-benzoyl) ATP led to significant reductions in glutamate-induced neuronal cell death, and that either TNF-alpha converting enzyme inhibitor or anti-TNF readily suppressed the protective effect implied by this result. Together, these findings indicate that both ERK and JNK are involved in the regulation of TNF mRNA expression, that p38 is involved in the nucleocytoplasmic transport of TNF mRNA, and that a PTK (protein tyrosine kinase), possibly a member of the src family, acts downstream of the P2X7 receptor to activate JNK and p38. Finally, our data suggest that P2X7 receptor-activated microglia protect neurons against glutamate toxicity primarily because they are able to release TNF.

Active Transport, Cell Nucleus↗

PubMed2004

Neuron-microglia communication in the CNS of the freshwater snail Planorbarius corneus.

The aim of the present study was to identify molecules that may be involved in neuron-microglia communication in the CNS of freshwater snail Planorbarius corneus. Messenger molecules are exchanged in normal and pathological conditions and we tried to identify some of them by immunocytochemistry on whole ganglia and cell cultures. In particular, we examined neurons and microglia for the expression of some cytokines, IL-1alpha, IL-1beta, IL-6 and TNF-alpha and the neurotransmitter glutamate. These substances may be released by suffering or injured neurons and communicate to microglia the damaging event. Even microglia, on own turn, once activated, express and released the same or other substances in order to reestablish the system homeostasis, depending on modalities and times of activation. We discuss the possibility that hyperactivated microglia can shift from neuroprotective to neurodegenerative. Moreover, we examined in neuron-microglia co-coltures the direct interaction effects in terms of neuronal survival and improved neurite regeneration.

Animals↗