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  • 1
    Keywords: RECEPTOR ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; PROTECTION ; CELL ; Germany ; MODEL ; MODELS ; NF-KAPPA-B ; ACTIVATION ; CELL ACTIVATION ; MECHANISM ; TRANSCRIPTION FACTOR ; mechanisms ; DELETION ; STEPS ; SIGNALING PATHWAYS ; PRODUCT ; SUPERFAMILY ; innate immunity ; Jun ; SOLUBLE RECEPTOR ; immune response ; IMMUNE-RESPONSE ; RECEPTORS ; INITIATION ; inflammation ; ANIMAL-MODELS ; immunoglobulin ; PRODUCTS ; LEADS ; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ; pattern recognition ; CLASS-III REGION ; DIABETIC VASCULOPATHY ; INFLAMMATORY RESPONSES
    Abstract: While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation
    Type of Publication: Journal article published
    PubMed ID: 15173891
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  • 2
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; INHIBITION ; GENE ; GENE-EXPRESSION ; MICE ; TIME ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; TRANSCRIPTION FACTOR ; INDUCTION ; gene expression ; FIBER ; PRODUCT ; LIGANDS ; SUPERFAMILY ; GLYCATION END-PRODUCTS ; PROGRAMMED CELL-DEATH ; ALPHA-LIPOIC ACID ; microenvironment ; PAIN ; EPSILON-CARBOXYMETHYLLYSINE ; immunoglobulin ; NEUROPATHY ; OXIDATIVE-STRESS ; PERIPHERAL-NERVE ; PRODUCTS
    Abstract: Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches
    Type of Publication: Journal article published
    PubMed ID: 15599399
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  • 3
    Keywords: brain ; PEPTIDE ; RECEPTOR ; CELLS ; EXPRESSION ; BLOOD ; CELL ; IN-VIVO ; INHIBITION ; MODEL ; NEW-YORK ; ACCUMULATION ; MICE ; BLOOD-FLOW ; blood flow ; FLOW ; ALZHEIMERS-DISEASE ; cytokines ; TARGET ; TRANSPORT ; MOUSE ; TRANSGENIC MICE ; STRESS ; transgenic ; PRODUCT ; RAGE ; CEREBRAL-BLOOD-FLOW ; CEREBROSPINAL-FLUID ; CLEARANCE ; DEMENTIA ; INTERACTS ; MOUSE MODEL ; PARENCHYMA ; PRECURSOR PROTEIN ; SQUIRREL-MONKEY ; TRANSGENIC MODEL ; VASCULATURE ; WALL
    Abstract: Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis
    Type of Publication: Journal article published
    PubMed ID: 12808450
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  • 4
    Keywords: PEPTIDE ; CELLS ; IN-VITRO ; CELL ; COMBINATION ; Germany ; VITRO ; SYSTEM ; MICE ; TIME ; ACTIVATION ; MECHANISM ; MARKER ; INDUCTION ; animals ; ANTIGEN ; DENDRITIC CELLS ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; TOLERANCE ; MOLECULE ; DELETION ; NERVOUS-SYSTEM ; TRANSGENIC MICE ; PROGRESSION ; NUMBER ; MARKERS ; CENTRAL-NERVOUS-SYSTEM ; MULTIPLE-SCLEROSIS ; T lymphocytes ; AUTOIMMUNE ENCEPHALOMYELITIS ; AUTOIMMUNITY ; thymus ; THYMIC EPITHELIAL-CELLS ; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ; MS ; multiple sclerosis ; immunology ; regulatory T cells ; animal ; nervous system ; central nervous system ; ANTIGEN RECOGNITION ; AUTOREACTIVE T-CELLS ; BASIC-PROTEIN GENE ; CD4(+) T cell ; RECEPTOR-ALPHA CHAINS ; TOLERANCE INDUCTION
    Abstract: Most autoantigens implicated in multiple sclerosis (MS) are expressed not only in the central nervous system (CNS) but also in the thymus and the periphery. Nevertheless, these autoantigens might induce a strong autoimmune response leading to severe destruction within the CNS. To investigate the influence of a dominantly presented autoantigen on experimental autoimmune encephalomyelitis (EAE), we generated transgenic mice expressing the autoantigenic peptide MBP1-10 covalently bound to the MHC class II molecule I-A(u). These mice were crossed either with B10.PL or with TCR-transgenic Tg4 mice, specific for the transgenic peptide-MHC combination. In double transgenic mice we found strong thymic deletion and residual peripheral T cells were refractory to antigen stimulation in vitro. Residual peripheral CD4(+) T cells expressed activation markers and a high proportion was CD25 positive. Transfer of both CD25-negative and CD25-positive CD4(+) T cells from double transgenic animals into B10.PL mice strongly inhibited the progression of EAE. Despite this thorough tolerance induction, some double transgenic mice developed severe signs of EAE after an extended period of time. Our data show that in the circumstances where autoantigenic priming persists, and where the number of antigen-specific T cells is high enough, autoimmunity may prevail over very potent tolerance-inducing mechanisms
    Type of Publication: Journal article published
    PubMed ID: 16361316
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  • 5
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; proliferation ; CELL ; CELL-PROLIFERATION ; NEW-YORK ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; MICE ; INJURIES ; LIGAND ; SUPPRESSION ; SIGNAL ; antibodies ; antibody ; TARGET ; PROMOTER ; AGE ; WILD-TYPE ; PRODUCT ; EXTRACELLULAR-MATRIX ; MUSCLE ; MIGRATION ; LIGANDS ; SMOOTH-MUSCLE CELLS ; E-NULL MICE ; GLYCATION END-PRODUCTS ; RAGE ; APOLIPOPROTEIN-E ; WALL ; MATRIX PROTEIN ; SMOOTH-MUSCLE ; INJURY ; AMYLOID-BETA-PEPTIDE ; BALLOON INJURY ; CALCIUM-BINDING PROTEINS ; CHEMOTACTIC S100 PROTEIN ; MMP ; RAT CAROTID-ARTERY
    Abstract: Cellular proliferation, migration, and expression of extracellular matrix proteins and MMPs contribute to neointimal formation upon vascular injury. Wild-type mice undergoing arterial endothelial denudation displayed striking upregulation of receptor for advanced glycation end products (RAGE) in the injured vessel, particularly in activated smooth muscle cells of the expanding neointima. In parallel, two of RAGE's signal transducing ligands, advanced glycation end products (AGES) and S100/calgranulins, demonstrated increased deposition/expression in the injured vessel wall. Blockade of RAGE, employing soluble truncated receptor or antibodies, or in homozygous RAGE null mice, resulted in significantly decreased neointimal expansion after arterial injury and decreased smooth muscle cell proliferation, migration, and expression of extracellular matrix proteins. A critical role for smooth muscle cell RAGE signaling was demonstrated in mice bearing a transgene encoding a RAGE cytosolic tail-deletion mutant, specifically in smooth muscle cells, driven by the SM22alpha promoter. Upon arterial injury, neointimal expansion was strikingly suppressed compared with that observed in wild-type littermates. Taken together, these data highlight key roles for RAGE in modulating smooth muscle cell properties after injury and suggest that RAGE is a logical target for suppression of untoward neointimal expansion consequent to arterial injury
    Type of Publication: Journal article published
    PubMed ID: 12671045
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  • 6
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; ENDOTHELIAL GROWTH-FACTOR ; NEW-YORK ; ACCUMULATION ; MICE ; TIME ; ACTIVATION ; MESANGIAL CELLS ; renal function ; RENAL-FUNCTION ; mechanisms ; MEMBRANE ; AGE ; PATHOGENESIS ; DISPLAY ; BINDING-PROTEINS ; GLYCATION END-PRODUCTS ; GROWTH-FACTOR-BETA ; pathology ; PROGRESSIVE NEPHROPATHIES ; OXIDANT STRESS ; CELL-SURFACE RECEPTOR ; FACTOR-BETA ; MATRIX GENE-EXPRESSION ; PASSIVE HEYMANN NEPHRITIS
    Abstract: Diabetic nephropathy ensues from events involving earliest changes in the glomeruli and podocytes, followed by accumulation of extracellular matrix in the mesangium. Postulated mechanisms include roles for vascular endothelial growth factor (VEGF), produced by podocytes and contributing to enhanced excretion of urinary albumin and recruitment/activation of inflammatory cells, and transforming growth factor-beta (TGF-beta), elicited largely from mesangial cells and driving production of extracellular matrix. RAGE, a receptor for advanced glycation endproducts (AGES) and S100/calgranulins, displays enhanced expression in podocytes of genetically diabetic db/db mice by age 13 weeks. RAGE-bearing podocytes express high levels of VEGF by this time, in parallel with enhanced recruitment of mononuclear phagocytes to the glomeruli; events prevented by blockade of RAGE. By age 27 weeks, soluble RAGE-treated db/db mice displayed diminished albuminuria and glomerulosclerosis, and improved renal function. Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane. We propose that activation of RAGE contributes to expression of VEGF and enhanced attraction/activation of inflammatory cells in the diabetic glomerulus, thereby setting the stage for mesangial activation and TGF-beta production; processes which converge to cause albuminuria and glomerulosclerosis
    Type of Publication: Journal article published
    PubMed ID: 12651605
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  • 7
    Keywords: RECEPTOR ; GENE-EXPRESSION ; MARKER ; T-CELLS ; DELETION ; TRANSGENIC MICE ; GREEN FLUORESCENT PROTEIN ; STRAIN ; END-PRODUCTS
    Abstract: The use of the Cre/loxP system has greatly empowered the field of gene targeting. Here we describe the successful establishment of a novel knock-in EGFP reporter mouse line to monitor Cre-induced recombination in the vast majority of cell types. The value of this reporter mouse line is demonstrated by the use of a novel Tie2Cre transgenic mouse line that facilitates gene targeting in endothelial and hematopoietic cells. High efficiency of recombination was found in all endothelial cells and in the majority of hematopoietic cells but was absent in other tissues. Furthermore, in the second generation, the Tie2Cre mouse can be used to get 100% recombination of one allele, whilst allowing tissue specific in the second, therefore offering excellent efficiency.
    Type of Publication: Journal article published
    PubMed ID: 11353516
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