155 research outputs found
Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons
The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions
Clusters of galaxies : observational properties of the diffuse radio emission
Clusters of galaxies, as the largest virialized systems in the Universe, are
ideal laboratories to study the formation and evolution of cosmic
structures...(abridged)... Most of the detailed knowledge of galaxy clusters
has been obtained in recent years from the study of ICM through X-ray
Astronomy. At the same time, radio observations have proved that the ICM is
mixed with non-thermal components, i.e. highly relativistic particles and
large-scale magnetic fields, detected through their synchrotron emission. The
knowledge of the properties of these non-thermal ICM components has increased
significantly, owing to sensitive radio images and to the development of
theoretical models. Diffuse synchrotron radio emission in the central and
peripheral cluster regions has been found in many clusters. Moreover
large-scale magnetic fields appear to be present in all galaxy clusters, as
derived from Rotation Measure (RM) studies. Non-thermal components are linked
to the cluster X-ray properties, and to the cluster evolutionary stage, and are
crucial for a comprehensive physical description of the intracluster medium.
They play an important role in the cluster formation and evolution. We review
here the observational properties of diffuse non-thermal sources detected in
galaxy clusters: halos, relics and mini-halos. We discuss their classification
and properties. We report published results up to date and obtain and discuss
statistical properties. We present the properties of large-scale magnetic
fields in clusters and in even larger structures: filaments connecting galaxy
clusters. We summarize the current models of the origin of these cluster
components, and outline the improvements that are expected in this area from
future developments thanks to the new generation of radio telescopes.Comment: Accepted for the publication in The Astronomy and Astrophysics
Review. 58 pages, 26 figure
Overexpression and altered glycosylation of MUC1 in malignant mesothelioma
Current interest in the MUC1/EMA mucin relates to its role in malignancy, and its potential as a therapeutic target. MUC1/EMA expression has been observed in the majority of epithelioid mesotheliomas. However, little is known of the characteristics of MUC1/EMA in mesothelioma. Herein, we studied the cell surface and soluble expression of the MUC1/EMA glycoprotein, and determined the mRNA and genomic expression profiles in mesothelioma. We found that the anti-MUC1 antibody, E29, was the most diagnostically useful of seven antibody clones examined with a sensitivity of 84% (16 out of 19 cases) and no false positive results. MUC1 mRNA expression was significantly higher in mesothelioma samples than in benign mesothelial cells. No amplification of the MUC1 gene was observed by FISH. Seven of 9 mesothelioma samples expressed MUC1-secreted mRNA isoform in addition to the archetypal MUC1/transmembrane form. CA15.3 (soluble MUC1) levels were significantly higher in the serum of mesothelioma patients than in healthy controls but were not significantly different to levels in patients with benign asbestos-related disease. CA15-3 in effusions could differentiate malignant from benign effusions but were not specific for mesothelioma. Thus, as in other cancers, alterations in MUC1 biology occur in mesothelioma and these results suggest that specific MUC1 characteristics may be useful for mesothelioma diagnosis and should also be investigated as a potential therapeutic target
In Vivo Imaging Reveals Distinct Inflammatory Activity of CNS Microglia versus PNS Macrophages in a Mouse Model for ALS
Mutations in the enzyme superoxide dismutase-1 (SOD1) cause hereditary variants
of the fatal motor neuronal disease Amyotrophic lateral sclerosis (ALS).
Pathophysiology of the disease is non-cell-autonomous: neurotoxicity is derived
not only from mutant motor neurons but also from mutant neighbouring
non-neuronal cells. In vivo imaging by two-photon
laser-scanning microscopy was used to compare the role of
microglia/macrophage-related neuroinflammation in the CNS and PNS using
ALS-linked transgenic SOD1G93A mice. These mice contained labeled
projection neurons and labeled microglia/macrophages. In the affected lateral
spinal cord (in contrast to non-affected dorsal columns), different phases of
microglia-mediated inflammation were observed: highly reactive microglial cells
in preclinical stages (in 60-day-old mice the reaction to axonal transection was
∼180% of control) and morphologically transformed microglia that have
lost their function of tissue surveillance and injury-directed response in
clinical stages (reaction to axonal transection was lower than 50% of
control). Furthermore, unlike CNS microglia, macrophages of the PNS lack any
substantial morphological reaction while preclinical degeneration of peripheral
motor axons and neuromuscular junctions was observed. We present in
vivo evidence for a different inflammatory activity of microglia
and macrophages: an aberrant neuroinflammatory response of microglia in the CNS
and an apparently mainly neurodegenerative process in the PNS
N-Acetylgalactosaminyltransferase-14 as a potential biomarker for breast cancer by immunohistochemistry
Neuroprotective function for ramified microglia in hippocampal excitotoxicity
<p>Abstract</p> <p>Background</p> <p>Most of the known functions of microglia, including neurotoxic and neuroprotective properties, are attributed to morphologically-activated microglia. Resting, ramified microglia are suggested to primarily monitor their environment including synapses. Here, we show an active protective role of ramified microglia in excitotoxicity-induced neurodegeneration.</p> <p>Methods</p> <p>Mouse organotypic hippocampal slice cultures were treated with <it>N</it>-methyl-D-aspartic acid (NMDA) to induce excitotoxic neuronal cell death. This procedure was performed in slices containing resting microglia or slices that were chemically or genetically depleted of their endogenous microglia.</p> <p>Results</p> <p>Treatment of mouse organotypic hippocampal slice cultures with 10-50 μM <it>N</it>-methyl-D-aspartic acid (NMDA) induced region-specific excitotoxic neuronal cell death with CA1 neurons being most vulnerable, whereas CA3 and DG neurons were affected less. Ablation of ramified microglia severely enhanced NMDA-induced neuronal cell death in the CA3 and DG region rendering them almost as sensitive as CA1 neurons. Replenishment of microglia-free slices with microglia restored the original resistance of CA3 and DG neurons towards NMDA.</p> <p>Conclusions</p> <p>Our data strongly suggest that ramified microglia not only screen their microenvironment but additionally protect hippocampal neurons under pathological conditions. Morphological activation of ramified microglia is thus not required to influence neuronal survival.</p
Expression site of P2RY12 in residential microglial cells in astrocytomas correlates with M1 and M2 marker expression and tumor grade
Rise and Fall of an Anti-MUC1 Specific Antibody
So far, human antibodies with good affinity and specificity for MUC1, a transmembrane protein overexpressed on breast cancers and ovarian carcinomas, and thus a promising target for therapy, were very difficult to generate.A human scFv antibody was isolated from an immune library derived from breast cancer patients immunised with MUC1. The anti-MUC1 scFv reacted with tumour cells in more than 80% of 228 tissue sections of mamma carcinoma samples, while showing very low reactivity with a large panel of non-tumour tissues. By mutagenesis and phage display, affinity of scFvs was increased up to 500fold to 5,7×10(-10) M. Half-life in serum was improved from below 1 day to more than 4 weeks and was correlated with the dimerisation tendency of the individual scFvs. The scFv bound to T47D and MCF-7 mammalian cancer cell lines were recloned into the scFv-Fc and IgG format resulting in decrease of affinity of one binder. The IgG variants with the highest affinity were tested in mouse xenograft models using MCF-7 and OVCAR tumour cells. However, the experiments showed no significant decrease in tumour growth or increase in the survival rates. To study the reasons for the failure of the xenograft experiments, ADCC was analysed in vitro using MCF-7 and OVCAR3 target cells, revealing a low ADCC, possibly due to internalisation, as detected for MCF-7 cells.Antibody phage display starting with immune libraries and followed by affinity maturation is a powerful strategy to generate high affinity human antibodies to difficult targets, in this case shown by the creation of a highly specific antibody with subnanomolar affinity to a very small epitope consisting of four amino acids. Despite these "best in class" binding parameters, the therapeutic success of this antibody was prevented by the target biology
Radiation-Induced c-Jun Activation Depends on MEK1-ERK1/2 Signaling Pathway in Microglial Cells
Radiation-induced normal brain injury is associated with acute and/or chronic inflammatory responses, and has been a major concern in radiotherapy. Recent studies suggest that microglial activation is a potential contributor to chronic inflammatory responses following irradiation; however, the molecular mechanism underlying the response of microglia to radiation is poorly understood. c-Jun, a component of AP-1 transcription factors, potentially regulates neural cell death and neuroinflammation. We observed a rapid increase in phosphorylation of N-terminal c-Jun (on serine 63 and 73) and MAPK kinases ERK1/2, but not JNKs, in irradiated murine microglial BV2 cells. Radiation-induced c-Jun phosphorylation is dependent on the canonical MEK-ERK signaling pathway and required for both ERK1 and ERK2 function. ERK1/2 directly interact with c-Jun in vitro and in cells; meanwhile, the JNK binding domain on c-Jun is not required for its interaction with ERK kinases. Radiation-induced reactive oxygen species (ROS) potentially contribute to c-Jun phosphorylation through activating the ERK pathway. Radiation stimulates c-Jun transcriptional activity and upregulates c-Jun-regulated proinflammatory genes, such as tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2. Pharmacologic blockade of the ERK signaling pathway interferes with c-Jun activity and inhibits radiation-stimulated expression of c-Jun target genes. Overall, our study reveals that the MEK-ERK1/2 signaling pathway, but not the JNK pathway, contributes to the c-Jun-dependent microglial inflammatory response following irradiation
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