RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease

Bucciarelli, Loredana; Wendt, Thoralf; Rong, Ling; Lalla, Evanthia; Hofmann, M.; Goova, Mouza T.; Taguchi, Akihiko; Yan, Shi Fang; Yan, Shi Du; Stern, David M.; Schmidt, Ann‐Marie

doi:10.1007/s00018-002-8491-x

Cited by 282 publications

(210 citation statements)

References 71 publications

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“…1 The RAGE (receptor of AGEs), a multi-ligand member of the immunoglobulin superfamily of transmembrane cell surface molecules, is a specific membrane-bound receptor for AGEs, 2 and activation of the RAGE by AGEs has a major role in the pathogenesis of diabetic vascular complications by way of activation of the NF kb (nuclear factor kb) pathway. 3 sRAGE is the soluble receptor of RAGE existing in the circulation.…”

Section: Introductionmentioning

confidence: 99%

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

Höllerl

et al. 2012

Int J Obes

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OBJECTIVE:The increased cardiovascular (CV) disease risk in patients with morbid obesity (MO) cannot be fully explained by traditional CV risk factors. Activation of the receptor of Advanced Glycation Endproducts (RAGE) leads to inflammation via the NF kb (nuclear factor kb) pathway. The soluble form of RAGE (sRAGE), which is present in plasma, can bind to ligands of RAGE and avoids interaction of RAGE with proinflammatory ligands. We investigated sRAGE levels in patients with MO and compared them with healthy lean controls (CO), before and after bariatric surgery. DESIGN: We conducted a cross-sectional study and a 24-month longitudinal study. SUBJECTS: We included 85 patients (mean age: 41±12 years; mean body mass index (BMI): 45.4±7.9 kg m À 2 ) with MO in comparison with 40 CO (mean age: 42 ± 13 years; mean BMI: 26.0 ± 5.5 kg m À 2 ). All patients were investigated before and 2 years after bariatric surgery. Apart from weight and CV risk markers (blood pressure, lipids), a glucose tolerance test (75 g), renal and inflammation parameters were assessed. sRAGE levels were assessed by a commercial ELISA. To investigate the associations of the observed reductions of values, delta (D) of parameters were calculated. RESULTS: Patients with MO had significant lower sRAGE levels than CO: 1010 ± 514 vs 1501 ± 674 pg ml À 1 ; Po0.001. In the longitudinal study, sRAGE levels increased significantly after bariatric surgery from 1010±514 to 1261±710 pg ml À 1 ; P ¼ 0.008. In the correlation analysis, DsRAGE levels were associated with D1-h and D2-h postprandial glucose, Dfasting insulin, D2-h postprandial insulin, DHOMA (homeostatic model assessment)-insulin resistance (DHOMA-IR), Dg-glutamyl transferase and Dtriglycerides. In a multivariate model, D1-h and D2-h postprandial glucose, D2-h postprandial insulin and DHOMA-IR predicted DsRAGE. CONCLUSION: Patients with MO have significantly lower sRAGE levels compared with non-obese CO, but sRAGE levels increase significantly after weight loss induced by bariatric surgery. As high sRAGE levels inhibit the activation of inflammatory pathways, our results might help understand the beneficial effects of bariatric surgery regarding CV morbidity and mortality. Keywords: morbid obesity; sRAGE; insulin resistance; prospective INTRODUCTION Hyperglycemia leads to non-enzymatic glycation of intracellular and extracellular protein by forming advanced glycation endproducts (AGEs). 1 The RAGE (receptor of AGEs), a multi-ligand member of the immunoglobulin superfamily of transmembrane cell surface molecules, is a specific membrane-bound receptor for AGEs, 2 and activation of the RAGE by AGEs has a major role in the pathogenesis of diabetic vascular complications by way of activation of the NF kb (nuclear factor kb) pathway. 3 sRAGE is the soluble receptor of RAGE existing in the circulation. sRAGE levels have been found to be associated with chronic inflammatory diseases, including atherosclerosis and diabetes. 4-6 sRAGE acts as a decoy to prevent an interaction between AGE and RAGE and ther...

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Section: Introductionmentioning

confidence: 99%

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

Höllerl

et al. 2012

Int J Obes

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“…10 RAGE has been implicated as a receptor mediating the chemotaxis and cytokine activity of HMGB1 in both Mϕ and tumor cells. 11 RAGE engagement by multiple Figure 1 Tissue damage suppresses LPS-induced monocytes/Mϕ necroptosis.…”

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Tissue damage negatively regulates LPS-induced macrophage necroptosis

Scott

Fan

et al. 2016

Cell Death Differ

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Infection is a common clinical complication following tissue damage resulting from surgery and severe trauma. Studies have suggested that cell pre-activation by antecedent trauma/tissue damage profoundly impacts the response of innate immune cells to a secondary infectious stimulus. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that control cell release of inflammatory mediators from important innate immune executive cells such as macrophages (Mϕ), which critically regulate the progress of inflammation. In this study, we investigated the mechanism and role of trauma/tissue damage in the regulation of LPS-induced Mϕ necroptosis using a mouse model simulating long-bone fracture. We demonstrate that LPS acting through Toll-like receptor (TLR) 4 promotes Mϕ necroptosis. However, necroptosis is ameliorated by high-mobility group box 1 (HMGB1) release from damaged tissue. We show that HMGB1 acting through cell surface receptor for advanced glycation end products (RAGE) upregulates caveolin-1 expression, which in turn induces caveolae-mediated TLR4 internalization and desensitization to decrease Mϕ necroptosis. We further show that RAGE-MyD88 activation of Cdc42 and subsequent activation of transcription factor Sp1 serves as a mechanism underlying caveolin-1 transcriptional upregulation. These results reveal a previous unidentified protective role of damage-associated molecular pattern (DAMP) molecules in restricting inflammation in response to exogenous pathogen-associated molecular pattern molecules.

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“…RAGE acts as a counter-receptor for several quite distinct classes of ligands, such as AGEs, S100/calgranulins, HMG1 (high mobility group 1 or amphoterin), and the family of crossed ␤-sheet fibrils/macromolecular assemblies, which activate receptormediated signal transduction pathways. These ligand-receptor interactions are believed to exert pathogenic effects through sustained cellular perturbation in a range of chronic disorders, including the secondary complications of diabetes, inflammation, and neurodegenerative processes (23,24). RAGE, a cell surface binding site for A␤ (25), is expressed at higher levels in an A␤-rich environment (26,27).…”

mentioning

confidence: 99%

RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction

Takuma

Fang

Zhang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

269

216

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Intracellular amyloid-␤ peptide (A␤) has been implicated in neuronal death associated with Alzheimer's disease. Although A␤ is predominantly secreted into the extracellular space, mechanisms of A␤ transport at the level of the neuronal cell membrane remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport of A␤ from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human A␤ subsequently showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice displayed decreased uptake of A␤ and protection from A␤-mediated mitochondrial dysfunction. A␤ activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of A␤-RAGE complex. Similar intraneuronal co-localization of A␤ and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate that RAGE contributes to mechanisms involved in the translocation of A␤ from the extracellular to the intracellular space, thereby enhancing A␤ cytotoxicity.is a progressive neurodegenerative process characterized by senile plaques, neurofibrillary tangles, and neuronal loss (1, 2). Deposition of amyloid-␤ peptide (A␤), a 39-43-amino acid peptide derived from the transmembrane amyloid precursor protein (APP), is found in extracellular senile plaque cores and is associated with neurodegeneration in later stages of AD. In contrast, recent studies suggest that accumulation of intraneuronal A␤ may be an early event in the pathogenesis of AD (3-16). Addition of A␤ to human neuronal-like cells caused significant mitochondrial damage (17). Furthermore, our recent study revealed that binding of A␤ to A␤-binding alcohol dehydrogenase (ABAD) or cyclophilin D (10, 11) intracellularly triggered events leading to neuronal apoptosis through a mitochondrial pathway (12,13,18,19). However, mechanisms through which A␤ produced at the plasma membrane and released into the extracellular space reaches the intracellular milieu remain to be elucidated.Receptor for advanced glycation end products (RAGE) is a multiligand receptor of the Ig superfamily of cell surface molecules (20)(21)(22). RAGE acts as a counter-receptor for several quite distinct classes of ligands, such as AGEs, S100/calgranulins, HMG1 (high mobility group 1 or amphoterin), and the family of crossed ␤-sheet fibrils/macromolecular assemblies, which activate receptormediated signal transduction pathways. These ligand-receptor interactions are believed to exert pathogenic effects through sustained cellular perturbation in a range of chronic disorders, including the secondary complications of diabetes, inflammation, and neurodegenerative processes (23,24). RAGE, a cell surface binding site for A␤ (25), is expressed at higher levels in an A␤-rich environment (...

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RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease

Cited by 282 publications

References 71 publications

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

Tissue damage negatively regulates LPS-induced macrophage necroptosis

RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction

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