Autocrine S100B effects on astrocytes are mediated via RAGE

Ponath, Gerald; Schettler, Christiane; Kaestner, Florian; Voigt, B.; Wentker, Dennis; Arolt, Volker; Rothermundt, Matthias

doi:10.1016/j.jneuroim.2006.12.011

Cited by 90 publications

(76 citation statements)

References 50 publications

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“…It is known that in response to cellular stress, S100␤ is released into the extracellular space where, similarly to HMGB1, it exhibits cytokine-like functions via RAGE-mediated NF-B transactivation. 83 However, in our experimental mouse model, we were unable to observe changes in expression or location of the S100␤ isoform in response to LPS. This may be explained by the low level of basal S100␤ expression observed in the mouse brain and liver at this stage of gestation.…”

Section: Damps and Fetal Inflammation 971mentioning

confidence: 69%

Characterization of RAGE, HMGB1, and S100β in Inflammation-Induced Preterm Birth and Fetal Tissue Injury

Buhimschi

Baumbusch

Dulay

et al. 2009

The American Journal of Pathology

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Immune activation represents an adaptive reaction triggered by both noxious exogenous (microbes) and endogenous [high mobility group box-1 protein (HMGB1), S100 calcium binding proteins] inducers of inflammation. Cell stress or necrosis lead the release of HMGB1 and S100 proteins in the extracellular compartment where they act as damage-associated molecular pattern molecules (or alarmins) by engaging the receptor for advanced glycation end-products (RAGE). Although the biology of RAGE is dictated by the accumulation of damage-associated molecular pattern molecules at sites of tissue injury, the role of RAGE in mediating antenatal fetal injury remains unknown. First, we studied the relationships at birth between the intensity of human fetal inflammation and sRAGE (an endogenous RAGE antagonist), HMGB1, and S100␤ protein. We found significantly lower sRAGE in human fetuses that mounted robust inflammatory responses. HMGB1 levels correlated significantly with levels of interleukin-6 and S100␤ in fetal circulation. We then evaluated the levels and areas of tissue expression of RAGE, HMGB1, and S100␤ in specific organs of mouse fetuses on E16. Using an animal model of endotoxin-induced fetal damage and preterm birth, we determined that inflammation induces a significant change in expression of RAGE and HMGB1, but not S100␤, at sites of tissue damage. Our findings indicate that RAGE and Conventional wisdom holds that the primary causes of the high neonatal morbidity and mortality attendant preterm birth are complications of immature organ systems.1-4 However, a growing body of investigation suggests that the poor outcome observed in many preterm children is not entirely dependent on their gestational age at birth. 2,5,6 After correcting for gestational age, several risk factors remain significantly associated with an increased risk of cerebral palsy, such as intra-amniotic infection, histological chorioamnionitis, prolonged rupture of the membranes, and hypoxemic fetal growth re-

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Section: Damps and Fetal Inflammation 971mentioning

confidence: 69%

Characterization of RAGE, HMGB1, and S100β in Inflammation-Induced Preterm Birth and Fetal Tissue Injury

Buhimschi

Baumbusch

Dulay

et al. 2009

The American Journal of Pathology

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“…By inducing neuronal death, S100B stimulates inflammatory stress as well as dispersal of interleukins (IL-1 [56], IL-6) and TNFα [57] and therefore might correlate with disease progression.…”

Section: Selection Of Blood Biomarkers In Ichmentioning

confidence: 99%

Potential Role of Blood Biomarkers in the Management of Nontraumatic Intracerebral Hemorrhage

Senn

Elkind

Montaner³

et al. 2014

Cerebrovasc Dis

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Background: Intracerebral hemorrhage (ICH), a subtype of stroke associated with high mortality and disability, accounts for 13% of all strokes. Basic and clinical research has contributed to our understanding of the complex pathophysiology of neuronal injury in ICH. Outcome rates, however, remain stable, and questions regarding acute management of ICH remain unanswered. Newer research is aiming at matching measured levels of serum proteins, enzymes, or cells to different stages of brain damage, suggesting that blood biomarkers may assist in acute diagnosis, therapeutic decisions, and prognostication. This paper provides an overview on the most promising blood biomarkers and their potential role in the diagnosis and management of spontaneous ICH. Summary: Information was collected from studies, reviews, and guidelines listed in PubMed up to November 2013 on blood biomarkers of nontraumatic ICH in humans.We describe the potential role and limitations of GFAP, S100B/RAGE, and ApoC-III as diagnostic biomarkers, F-Amyloid as a biomarker for etiological classification, and 27 biomarkers for prognosis of mortality and functional outcome. Within the group of prognostic markers we discuss markers involved in coagulation processes (e.g., D-Dimers), neuroendocrine markers (e.g., copeptin), systemic metabolic markers (e.g., blood glucose levels), markers of inflammation (e.g., IL-6), as well as growth factors (e.g., VEGF), and others (e.g., glutamate). Some of those blood biomarkers are agents of pathologic processes associated with hemorrhagic stroke but also other diseases, whereas others play more distinct pathophysiological roles and help in understanding the basic mechanisms of brain damage and/or recovery in ICH. Key Messages: Numerous blood biomarkers are associated with different pathophysiological pathways in ICH, and some of them promise to be useful in the management of ICH, eventually contributing additional information to current tools for diagnosis, therapy monitoring, risk stratification, or intervention. Up to date, however, no blood biomarker of ICH has been studied sufficiently to find its way into clinical routine yet; well-designed, large-scale, clinical studies addressing relevant clinical questions are needed. We suggest that the effectiveness of biomarker research in ICH might be improved by international cooperation and shared resources for large validation studies, such as provided by the consortium on stroke biomarker research (http://stroke-biomarkers.com/page.php?title=Resources). i 2014 S. Karger AG, Basel

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“…In vitro studies using primary neurons or neuroblastoma cells showed that stimulation of RAGE by low levels of S100B leads to neurite outgrowth, and activation of pro-survival pathways during stress conditions like trophic factor deprivation, glutamate, N-methyl-D-aspartate, or amyloid-␤ toxicity (9 -12). On the other hand, treatment of primary neurons, astrocytes, or microglia with relatively high doses of S100B leads to oxidative stress, NF-B activation, expression of proinflammatory mediators, and cytotoxicity (9,11,13,14). Little is…”

mentioning

confidence: 99%

Hypoxia-inducible Factor-1 Mediates Neuronal Expression of the Receptor for Advanced Glycation End Products following Hypoxia/Ischemia

Pichiule

Chávez

Schmidt

et al. 2007

Journal of Biological Chemistry

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Activation of the receptor for advanced glycation endproducts (RAGE) by its multiple ligands can trigger diverse signaling pathways with injurious or pro-survival consequences. In this study, we show that Rage mRNA and protein levels were stimulated in the mouse brain after experimental stroke and systemic hypoxia. In both cases, RAGE expression was primarily associated with neurons. Activation of RAGE-dependent pathway(s) post-ischemia appears to have a neuroprotective role because mice genetically deficient for RAGE exhibited increased infarct size 24 h after injury. Up-regulation of RAGE expression was also observed in primary neurons subjected to hypoxia or oxygen-glucose deprivation, an in vitro model of ischemia. Treatment of neurons with low concentrations of S100B decreased neuronal death after oxygen-glucose deprivation, and this effect was abolished by a neutralizing antibody against RAGE. Conversely, high concentrations of exogenous S100B had a cytotoxic effect that seems to be RAGE-independent. As an important novel finding, we demonstrate that hypoxic stimulation of RAGE expression is mediated by the transcription factor hypoxia-inducible factor-1. This conclusion is supported by the finding that HIF-1␣ down-regulation by Cre-mediated excision drastically decreased RAGE induction by hypoxia or desferrioxamine. In addition, we showed that the mouse RAGE promoter region contains at least one functional HIF-1 binding site, located upstream of the proposed transcription start site. A luciferase reporter construct containing this RAGE promoter fragment was activated by hypoxia, and mutation at the potential HIF-1 binding site decreased hypoxia-dependent promoter activation. Specific binding of HIF-1 to this putative HRE in hypoxic cells was detected by chromatin immunoprecipitation assay.The receptor for advanced glycation end products (RAGE) 4 is a member of the immunoglobin superfamily of cell surface molecules. It was originally identified by its capacity to bind advanced glycation end products, adducts that accumulate during natural aging and are produced at an augmented rate during diabetes (1). Subsequently, several other ligands for this receptor have been reported including amyloid-␤ peptide, high-mobility group box 1, some members of the S100/calgranulin family, and Mac-1 (2-5). Multiple studies indicate that RAGE signaling has profound stimulatory effects on gene expression of inflammatory mediators, a mechanism that has been implicated in the pathogenesis of diabetic complications in the periphery (for review, see Ref. 6). In the central nervous system, the expression of RAGE has been described in several cell types. During the embryonic and early postnatal period, RAGE is highly expressed by hippocampal, cortical, and cerebellar neurons (4). Expression of this receptor is limited in the normal adult brain, but enhanced in pathological conditions like Alzheimer disease (5, 7). In this pathology, RAGE expression was observed not only in neurons but also in endothelial cells, and microglia (5, 8...

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Autocrine S100B effects on astrocytes are mediated via RAGE

Cited by 90 publications

References 50 publications

Characterization of RAGE, HMGB1, and S100β in Inflammation-Induced Preterm Birth and Fetal Tissue Injury

Characterization of RAGE, HMGB1, and S100β in Inflammation-Induced Preterm Birth and Fetal Tissue Injury

Potential Role of Blood Biomarkers in the Management of Nontraumatic Intracerebral Hemorrhage

Hypoxia-inducible Factor-1 Mediates Neuronal Expression of the Receptor for Advanced Glycation End Products following Hypoxia/Ischemia

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