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  • EXPRESSION  (9)
  • 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: EXPRESSION ; SQUAMOUS-CELL CARCINOMA ; HEAD ; inflammation ; TUMOR-GROWTH ; BLOCKADE ; IMMUNE ; calprotectin ; ENDPRODUCTS RAGE ; S100A8/S100A9
    Abstract: Aberrant expression of the receptor for advanced glycation end products (RAGE) and its ligands, such as S100/Calgranulins, has been demonstrated in squamous cell carcinomas of the upper aerodigestive tract. However, the question whether RAGE signaling is causally linked with neoplastic transformation of keratinocytes in mucosal epithelia has not been addressed so far. We used the well-established mouse model of 4-nitroquinoline-1-oxide (4-NQO) induced tumorigenesis to investigate tumor development in control and RAGE-deficient (Rage(-/-)) animals. Although 4-NQO induced lesions of the tongue and the esophagus showed strong induction of the RAGE ligands S100a8 and S100a9, we did not observe any significant difference in tumor incidence or multiplicity between control and Rage(-/-) mice. Furthermore, detailed analysis of tumor sections by histological and immunohistochemical staining revealed no difference in either the size or histological architecture of dysplastic lesions, tumor cell proliferation, or the number of inflammatory immune cells in the tumor microenvironment. Finally, we detected induced transcript and protein levels of the Toll-like receptor 4 (Tlr4) in 4-NQO induced lesions, suggesting that signaling via the S100-Tlr4 axis may compensate for the lack of RAGE in early stages of tumor development. Our data demonstrate that RAGE is dispensable in the onset of genotoxic induced oral and esophageal squamous cell carcinoma and provide evidence for an alternative pathway of S100-Calgranulin signaling via Tlr4.
    Type of Publication: Journal article published
    PubMed ID: 23712426
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  • 3
    Keywords: RECEPTOR ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; MODEL ; PATHWAY ; VITRO ; NEW-YORK ; PROTEIN ; PROTEINS ; MICE ; DISORDER ; RECOGNITION ; WILD-TYPE ; ADHESION ; RECRUITMENT ; ADHESION MOLECULE-1 ; BINDING-PROTEINS ; diabetes ; DIABETIC-RATS ; E-NULL MICE ; FACTOR-KAPPA-B ; GLYCATION END-PRODUCTS ; INTEGRIN ; leukocyte ; peritoneum ; RAGE ; SOLUBLE RECEPTOR ; TISSUE FACTOR ; UROKINASE RECEPTOR
    Abstract: The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the beta2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with beta1-integrins. The RAGE-Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric beta2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE-Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications
    Type of Publication: Journal article published
    PubMed ID: 14623906
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  • 4
    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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  • 5
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH-FACTOR ; BLOOD ; SUPPORT ; GENE-EXPRESSION ; TISSUE ; ACCUMULATION ; MICE ; ACTIVATION ; INJURIES ; LIGAND ; MESANGIAL CELLS ; MEMBER ; MOUSE ; AMPLIFICATION ; AGE ; SUPERFAMILY ; EPITHELIAL-CELLS ; BINDING-PROTEINS ; APOLIPOPROTEIN-E ; PROTEIN-KINASE-C ; GLUCOSE ; VESSELS ; ALDOSE REDUCTASE ; GLYCOSYLATION END-PRODUCTS ; OXIDANT STRESS ; PKC-BETA INHIBITOR
    Abstract: Receptor for advanced glycation endproducts (RAGE) is a multi- ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accumulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in diabetic tissues, upregulation and activation of RAGE magnifies cellular perturbation in tissues affected by hyperglycemia, such as the large blood vessels and the kidney. In the diabetic glomerulus, RAGE is expressed principally by glomerular visceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and structural alterations in the kidney, in the absence of alterations in blood glucose. Recent studies in homozygous RAGE null mice support a key role for RAGE in glomerular perturbation in diabetes. Importantly, beyond diabetes, studies in other settings of glomerulopathies support a critical RAGE-dependent pathway in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is propsed in glomerular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomerular injury in diabetes and other sclerosing glomerulopathies
    Type of Publication: Journal article published
    PubMed ID: 12707408
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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: CELLS ; EXPRESSION ; CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; PATHWAYS ; VOLUME ; DEATH ; transcription ; NF-KAPPA-B ; ACTIVATION ; LIGAND ; INDUCTION ; CONTRAST ; DENDRITIC CELLS ; LYMPH-NODES ; SIGNAL ; FORM ; DIFFERENCE ; CELL-DEATH ; SIGNALING PATHWAYS ; MIGRATION ; ONCOGENE ; ATHEROSCLEROSIS ; immune response ; IMMUNE-RESPONSE ; PERIPHERAL-BLOOD ; CD4(+) T-CELLS ; F ; AUTOIMMUNITY ; CYTOKINE ; PERSISTENT ; NODES ; RE ; STRENGTH ; CD40 LIGAND ; CD40-CD40 LIGAND ; IL-12 PRODUCTION ; PHYSIOLOGICAL STIMULI
    Abstract: Migration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c(+) peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals. (C) 2004 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 15113760
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  • 8
    Keywords: RECEPTOR ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; tumor ; CELL ; Germany ; IN-VIVO ; SUPPORT ; NEW-YORK ; TISSUE ; MICE ; LIGAND ; MECHANISM ; CARCINOGENESIS ; KERATINOCYTES ; mechanisms ; SKIN ; BONE-MARROW ; PROGRESSION ; MOUSE SKIN ; skin carcinogenesis ; LIGANDS ; FACTOR-KAPPA-B ; GLYCATION END-PRODUCTS ; inflammation ; signaling ; molecular ; RE ; CANCER DEVELOPMENT ; PHASE ; USA ; BONE ; immunology ; PROMOTES ; MEDICINE ; DOUBLE-EDGED-SWORD
    Abstract: A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting micro-environment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinflammatory mediators, maintenance of immune cell infiltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic inflammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infiltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an inflammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic inflammation and cancer
    Type of Publication: Journal article published
    PubMed ID: 18208974
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  • 9
    Keywords: EXPRESSION ; ACTIVATION ; BLOOD-FLOW ; RAT ; inactivation ; NEURONS ; FOREBRAIN ; GLYOXALASE-I ; PERIPHERAL NEUROPATHY ; RESISTANT SODIUM-CHANNELS ; ROOT GANGLION NEURONS ; SENSITIVE METHOD
    Abstract: This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal-and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy
    Type of Publication: Journal article published
    PubMed ID: 22581285
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