Neuroinflammatory Diseases (neuroinflammatory + disease)

Distribution by Scientific Domains

Selected Abstracts

AUF-1 mediates inhibition by nitric oxide of lipopolysaccharide-induced matrix metalloproteinase-9 expression in cultured astrocytes

Wenlan Liu
Abstract Neuroinflammatory diseases are associated with increased production of matrix metalloproteinase-9 (MMP-9) and excessive generation of nitric oxide (NO). NO hasbeen reported to have variable effects on MMP-9 gene expression and activation in various cell types. Inthe present study, we investigated the effect of NOon MMP-9 expression in primary cortical astrocytes. Zymography and real-time PCR showed that lipopolysaccharide (LPS) dramatically increased latent MMP-9 gelatinolytic activity and MMP-9 mRNA expression. By using the NO donor DETA NONOate, we observed a dose-dependent inhibition of MMP-9 induction by LPS. Active forms of MMP-9 were not found by zymography after NO treatment. The MEK1/2 inhibitor U0126 completely inhibited LPS-induced MMP-9, which was partially inhibited by the p38 MAPK inhibitor SB203580. NO had no effect on LPS-stimulated ERK1/2 and p38 MAPK activation, suggesting that the inhibitory action of NO occurs downstream of MAPK cascades. Real-time PCR analysis showed that NO accelerated the degradation of MMP-9 mRNA after LPS induction. Western blotting and pull-down assay demonstrated that NO increased AUF-1 expression as well as its specific binding to the MMP-9 gene 3,-untranslated region. Knockdown of AUF-1 with siRNA partially reversed the inhibitory action of NO on LPS-stimulated MMP-9 induction. We conclude that NO does not activate MMP-9 in astrocyte cultures but reduces LPS-induced MMP-9 expression via accelerating MMP-9 mRNA degradation, which is partially mediated by AUF-1. Our results suggest that elevated NO concentrations may suppress MMP-9 and restrict the inflammatory response in neurodegenerative diseases. © 2006 Wiley-Liss, Inc. [source]

The level of B7 homologue 1 expression on brain DC is decisive for CD8 Treg cell recruitment into the CNS during EAE

Alla L. Zozulya
Abstract DC in the CNS have emerged as the major rate-limiting factor for immune invasion and subsequent neuroinflammation during EAE. The mechanism of how this is regulated by brain-localized DC remains unknown. Here, we describe the ability of brain-localized DC expressing B7-H1 molecules to recruit CD8+ T cells to the site of inflammation. Using intracerebral microinjections of B7-homologue 1-deficient DC, we demonstrate a substantial brain infiltration of CD8+ T cells displaying a regulatory phenotype (CD122+) and function, resulting in a decrease of EAE peak clinical values. The recruitment of regulatory-type CD8+ T cells into the CNS and the role of brain DC expressing B7-homologue 1 molecules in this process open up the possibility of DC-targeted therapeutic manipulation of neuroinflammatory diseases. [source]

Dexamethasone suppresses monocyte chemoattractant protein-1 production via mitogen activated protein kinase phosphatase-1 dependent inhibition of Jun N-terminal kinase and p38 mitogen-activated protein kinase in activated rat microglia

Yan Zhou
Abstract Microglial cells release monocyte chemoattractant protein-1 (MCP-1) which amplifies the inflammation process by promoting recruitment of macrophages and microglia to inflammatory sites in several neurological diseases. In the present study, dexamethasone (Dex), an anti-inflammatory and immunosuppressive drug has been shown to suppress the mRNA and protein expression of MCP-1 in activated microglia resulting in inhibition of microglial migration. This has been further confirmed by the chemotaxis assay which showed that Dex or MCP-1 neutralization with its antibody inhibits the microglial recruitment towards the conditioned medium of lipopolysaccharide (LPS)-treated microglial culture. This study also revealed that the down-regulation of the MCP-1 mRNA expression by Dex in activated microglial cells was mediated via mitogen-activated protein kinase (MAPK) pathways. It has been demonstrated that Dex inhibited the phosphorylation of Jun N-terminal kinase (JNK) and p38 MAP kinases as well as c-jun, the JNK substrate in microglia treated with LPS. The involvement of JNK and p38 MAPK pathways in induction of MCP-1 production in activated microglial cells was confirmed as there was an attenuation of MCP-1 protein release when microglial cells were treated with inhibitors of JNK and p38. In addition, Dex induced the expression of MAP kinase phosphatase-1 (MKP-1), the negative regulator of JNK and p38 MAP kinases in microglial cells exposed to LPS. Blockade of MKP-1 expression by triptolide enhanced the phosphorylation of JNK and p38 MAPK pathways and the mRNA expression of MCP-1 in activated microglial cells treated with Dex. In summary, Dex inhibits the MCP-1 production and subsequent microglial cells migration to the inflammatory site by regulating MKP-1 expression and the p38 and JNK MAPK pathways. This study reveals that the MKP-1 and MCP-1 as novel mediators of biological effects of Dex may help developing better therapeutic strategies for the treatment of patients with neuroinflammatory diseases. [source]

Interleukin-12 P40 induces the expression of TNF-, in microglia and macrophages

M. Jana
Recently, it has been found that overproduction of IL-12 can be dangerous to the host as it is involved in the pathogenesis of a number of autoimmune inflammatory diseases such as multiple sclerosis. It is composed of two different subunits , p40 and p35. Expression of p40 mRNA but not that of p35 mRNA in excessive amount in the CNS of patients with Multiple Sclerosis (MS) suggests that IL-12 p40 may have a role in the pathogenesis of the disease. The present study was undertaken to explore the role of p40 in the expression of TNF-, in microglia. Interestingly, we have found that IL-12 p70, p402 (the p40 homodimer) and p40 (the p40 monomer) dose-dependently induced the production of TNF-, in BV-2 microglial cells. This induction of TNF-, production was accompanied by an induction of TNF-, mRNA. In addition to BV-2 glial cells, p70, p402 and p40 also induced the production of TNF-, in mouse primary microglia and peritoneal macrophages. Since the activation of both NF-,B and C/EBPb is important for the expression of TNF-, in microglial cells, we investigated the effect of p40 on the activation of NF-,B as well as C/EBPb. Activation of NF-,B as well as C/EBPb by p40 and inhibition of p40-induced expression of TNF-, by Dp65, a dominant-negative mutant of p65, and DC/EBPb, a dominant-negative mutant of C/EBPb, suggests that p40 induces the expression of TNF-, through the activation of NF-,B and C/EBPb. This study delineates a novel role of IL-12 p40 in inducing the expression of TNF-, in microglial cells which may participate in the pathogenesis of neuroinflammatory diseases. Acknowledgements:, This study was supported by NIH grants (NS39940 and AG19487). [source]

Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity , a tale of conflict and conundrum

M. Müller
M. Müller, S. Carter, M. J. Hofer and I. L. Campbell (2010) Neuropathology and Applied Neurobiology36, 368,387 The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity , a tale of conflict and conundrum The chemokines CXCL9, CXCL10 and CXCL11 (also known as monokine induced by interferon-,, interferon-inducible protein-10 and interferon-inducible T cell ,-chemoattractant, respectively) are structurally and functionally related molecules within the non-ELR CXC chemokine subgroup. These chemokines are generally not detectable in most non-lymphoid tissues under physiological conditions but are strongly induced by cytokines, particularly interferon-,, during infection, injury or immunoinflammatory responses. CXCL9, CXCL10 and CXCL11 each bind to a common primary receptor, CXCR3, and possibly to additional receptors. They are best known for their role in leucocyte trafficking, principally acting on activated CD4+ Th1 cells, CD8+ T cells and NK cells. An abundance of data demonstrates that CXCL9, CXCL10 and CXCL11 are produced in many diverse pathologic conditions of the central nervous system. More recent attention has focussed on the function of these chemokines in the central nervous system inflammation. The results of these studies have proven to be sometimes surprising and other times contradictory. Here we discuss the likely more subtle and perhaps divergent roles for these chemokines in the pathogenesis of neuroinflammatory diseases. [source]

Neuronal FasL Induces Cell Death of Encephalitogenic T Lymphocytes

A. Flügel
Apoptosis of inflammatory cells plays a crucial role in the recovery from autoimmune CNS disease. However, the underlying mechanisms of apoptosis induction are as yet ill-defined. Here we report on the neuronal expression of FasL and its potential function in inducing T-cell apoptosis. Using a combination of facial nerve axotomy and passive transfer encephalomyelitis, the fate of CD4+ encephalitogenic T cells engineered to express the gene for green fluorescent protein was followed. FasL gene transcripts and FasL protein were detected in neurons by in situ -hybridization and immunohistochemistry. T cells infiltrating preferentially the injured brain parenchyma were found in the immediate vicinity of FasL expressing neurons and even inside their perikarya. In contrast to neurons, T cells rapidly underwent apoptosis. In co-cultures of hippocampal nerve cells and CD4+ T lymphocytes, we confirmed expression of FasL in neurons and concomitant induction of T-cell death. Antibodies blocking neuronal FasL were shown to have a protective effect on T-cell survival. Thus, FasL expression by neurons in neuroinflammatory diseases may constitute a pivotal mechanism underlying apoptosis of encephalitogenic T cells. [source]

Obovatol attenuates microglia-mediated neuroinflammation by modulating redox regulation

Jiyeon Ock
Background and purpose:, Obovatol isolated from the medicinal herb Magnolia obovata exhibits a variety of biological activities. Here, the effect of obovatol and its mechanism of action on microglial activation, neuroinflammation and neurodegeneration were investigated. Experimental approach:, In microglial BV-2 cells stimulated with lipopolysaccharide (LPS), we measured nitric oxide (NO) and cytokine production, and activation of intracellular signalling pathways by reverse transcription-polymerase chain reaction and Western blots. Cell death was assayed in co-cultures of activated microglia (with bacterial LPS) and neurons and in LPS-induced neuroinflammation in mice in vivo. Key results:, Obovatol inhibited microglial NO production with an IC50 value of 10 µM. Obovatol also inhibited microglial expression of proinflammatory cytokines and inducible nitric-oxide synthase, which was accompanied by the inhibition of multiple signalling pathways such as nuclear factor kappa B, signal transducers and activators of transcription 1, and mitogen-activated protein kinases. In addition, obovatol protected cultured neurons from microglial toxicity and inhibited neuroinflammation in mice in vivo. One molecular target of obovatol in microglia was peroxiredoxin 2 (Prx2), identified by affinity chromatography and mass spectrometry. Obovatol enhanced the reactive oxygen species (ROS)-scavenging activity of Prx2 in vitro, thereby suppressing proinflammatory signalling pathways of microglia where ROS plays an important role. Conclusions and implications:, Obovatol is not only a useful chemical tool that can be used to investigate microglial signalling, but also a promising drug candidate against neuroinflammatory diseases. Furthermore, our results indicate that Prx2 is a novel drug target that can be exploited for the therapeutic modulation of neuroinflammatory signalling. [source]