Clynes R, Moser B, Yan SF, et al. Receptor for AGE (RAGE): weaving tangled webs within the inflammatory response

Division of Surgical Science, Department of Surgery, Columbia University Medical Center, 630 West 168th Street, P&S 17-501, New York, NY 10032, USA.
Current Molecular Medicine (Impact Factor: 3.62). 01/2008; 7(8):743-51. DOI: 10.2174/156652407783220714
Source: PubMed

ABSTRACT The family of RAGE ligands, including Advanced Glycation Endproducts (AGEs), S100/calgranulins, High Mobility Group Box-1 (HMGB1) and amyloid beta peptide (Abeta) and beta-sheet fibrils are highly enriched in immune and inflammatory foci. In parallel, upregulation of Receptor for AGE (RAGE) is noted in diverse forms of inflammation and autoimmunity, based on experiments examining human tissues as well as animal models. Indeed, prior to the demonstration that S100/calgranulins were signal transduction ligands of RAGE, these molecules were considered "biomarkers" of disease and disease activity in disorders such as colitis and arthritis. Premiere roles for RAGE in advancing cellular migration implicate this receptor in targeting immune cells to vulnerable foci. Once engaged, ligand-RAGE interaction in inflammatory and vascular cells amplifies upregulation of inflammatory cytokines, adhesion molecules and matrix metalloproteinases (MMPs). Discerning the primal versus chronic injury-provoking roles for this ligand-receptor interaction is a challenge in delineating the functions of the ligand/RAGE axis. As RAGE is expressed by many of the key cell types linked integrally to the immune response, we propose that the sites and time course of ligand-RAGE stimulation determine the phenotype produced by this axis. Ultimately, drawing the fine line between antagonism versus stimulation of the receptor in health and disease will depend on the full characterization of RAGE in repair versus injury.

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    • "With respect to RAGE signaling, several target genes have been identified in the past, including proinflammetory mediators, matrix mataroproteinases and adhesion molecules. However, their expression critically depends on cell type, microenvironment and quality of the stimulus [24]. Additionally, although multiple intracellular signaling pathways, including MAP kinases, Rho GTPases, PI3K, JAK/STAT, and NF-κB, have been found to be altered following RAGE stimulation, the molecular mechanisms on how RAGE triggers intracellular signaling to regulate cellular decisions remain largely elusive and the identity of direct signaling molecules downstream of the receptor to modulate chondrocytes are still unknown [25]–[27]. "
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    ABSTRACT: RAGE, receptor for advanced glycation endoproducts (AGE), has been characterized as an activator of osteoclastgenesis. However, whether RAGE directly regulates chondrocyte proliferation and differentiation is unclear. Here, we show that RAGE has an inhibitory role in chondrocyte differentiation. RAGE expression was observed in chondrocytes from the prehypertrophic to hypertrophic regions. In cultured cells, overexpression of RAGE or dominant-negative-RAGE (DN-RAGE) demonstrated that RAGE inhibited cartilaginous matrix production, while DN-RAGE promoted production. Additionally, RAGE regulated Ihh and Col10a1 negatively but upregulated PTHrP receptor. Ihh promoter analysis and real-time PCR analysis suggested that downregulation of Cdxs was the key for RAGE-induced inhibition of chondrocyte differentiation. Overexpression of the NF-κB inhibitor I-κB-SR inhibited RAGE-induced NF-κB activation, but did not influence inhibition of cartilaginous matrix production by RAGE. The inhibitory action of RAGE was restored by the Rho family GTPases inhibitor Toxin B. Furthermore, inhibitory action on Ihh, Col10a1 and Cdxs was reproduced by constitutively active forms, L63RhoA, L61Rac, and L61Cdc42, but not by I-κB-SR. Cdx1 induced Ihh and Col10a1 expressions and directly interacted with Ihh promoter. Retinoic acid (RA) partially rescued the inhibitory action of RAGE. These data combined suggests that RAGE negatively regulates chondrocyte differentiation at the prehypertrophic stage by modulating NF-κB-independent and Rho family GTPases-dependent mechanisms.
    PLoS ONE 10/2014; 9(10):e108819. DOI:10.1371/journal.pone.0108819 · 3.23 Impact Factor
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    • "The receptor of advanced glycation endproducts (RAGE) is a transmembrane protein belonging to the immunoglobulin (Ig) superfamily, and after signal peptide cleavage is composed of an extracellular domain containing three Ig-like domains, a single transmembrane helix and a cytoplasmic tail [1]. RAGE acts as a pattern recognition receptor (PRR) involved in inflammation resolution leading to tissue repair or alternatively in its perpetuation leading to chronic inflammation [2]. RAGE binds a large variety of molecules, including the so called advanced glycation endproducts (AGEs) that give it its name. "
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    ABSTRACT: The human receptor for advanced glycation endproducts (RAGE) is a multiligand cell surface protein belonging to the immunoglobulin superfamily, and is involved in inflammatory and immune responses. Most importantly, RAGE is considered a receptor for HMGB1 and several S100 proteins, which are Damage-Associated Molecular Pattern molecules (DAMPs) released during tissue damage. In this study we show that the Ager gene coding for RAGE first appeared in mammals, and is closely related to other genes coding for cell adhesion molecules (CAMs) such as ALCAM, BCAM and MCAM that appeared earlier during metazoan evolution. RAGE is expressed at very low levels in most cells, but when expressed at high levels, it mediates cell adhesion to extracellular matrix components and to other cells through homophilic interactions. Our results suggest that RAGE evolved from a family of CAMs, and might still act as an adhesion molecule, in particular in the lung where it is highly expressed or under pathological conditions characterized by an increase of its protein levels.
    PLoS ONE 01/2014; 9(1):e86903. DOI:10.1371/journal.pone.0086903 · 3.23 Impact Factor
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    • "We also demonstrated its role in systemic vascular remodeling by activating STAT3/provirus integration site for Moloney murine leukemia virus/nuclear factor of activated T‐cell cascade stimulating smooth‐muscle cell proliferation and resistance to apoptosis through a calcium‐dependent mechanism.15 Indeed, from a molecular point of view, RAGE seems to be implicated in many signaling pathway such as inflammation, proliferation, and migration,16–19 which are all implicated in PAH etiology. Furthermore, in their recent proteomic analysis, the Wilkins team demonstrated that RAGE is one of the most upregulated proteins in PAH lung tissues compared with control lung tissues,20 leading to our hypothesis that RAGE is implicated in PAH etiology. "
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (STAT3)/bone morphogenetic protein receptor 2 (BMPR2)/peroxisome proliferator-activated receptor gamma (PPARγ) in PAH. STAT3 activation induces BMPR2 downregulation, decreasing PPARγ, which both contribute to the proproliferative and antiapoptotic phenotype seen in PAH. In chondrocytes, activation of this axis has been attributed to the advanced glycation end-products receptor (RAGE). As RAGE is one of the most upregulated proteins in PAH patients' lungs and a strong STAT3 activator, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation, promoting PAH-PASMC proliferation and resistance to apoptosis. In vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH-PASMC (6-fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6-fold, thus activating STAT3 and decreasing BMPR2 and PPARγ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline- and Sugen-induced PAH demonstrates therapeutic effects characterized by PA pressure and right ventricular hypertrophy decrease (control rats have an mPAP around 15 mm Hg, PAH rats have an mPAP >40 mm Hg, and with RAGE inhibition, mPAP decreases to 20 and 28 mm Hg, respectively, in MCT and Sugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR2/PPARγ axis restoration (increased by ≥60%). We have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH.
    Journal of the American Heart Association 12/2013; 2(1):e005157. DOI:10.1161/JAHA.112.005157 · 4.31 Impact Factor
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