RAGE: therapeutic target and biomarker of the inflammatory response—the evidence mounts

• Published in: Journal of leukocyte biology Vol. 86; no. 3; pp. 505 - 512
• Main Authors: Ramasamy, Ravichandran, Yan, Shi Fang, Schmidt, Ann Marie
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.09.2009
• Subjects: Biomarkers - blood; glycation; Glycation End Products, Advanced - genetics; Glycation End Products, Advanced - metabolism; HMGB1; Humans; inflammation; Inflammation - genetics; Inflammation - metabolism; Ligands; Models, Immunological; oxidation; Polymorphism, Single Nucleotide; Protein Binding - genetics; Protein Structure, Tertiary; Receptor for Advanced Glycation End Products; Receptors, Immunologic - blood; Receptors, Immunologic - chemistry; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; S100; Signal Transduction; Solubility
• ISSN: 0741-5400; 1938-3673; 1938-3673
• DOI: 10.1189/jlb.0409230

RAGE may be a biomarker and/or target for therapeutic intervention in chronic disease such as diabetes, inflammation, neurodegeneration, and tumors. The RAGE binds multiple ligand families linked to hyperglycemia, aging, inflammation, neurodegeneration, and cancer. Activation of RAGE by its ligands stimulates diverse signaling cascades. The recent observation that the cytoplasmic domain of RAGE interacts with diaphanous or mDia–1 links RAGE signal transduction to cellular migration and activation of the Rho GTPases, cdc42 and rac–1. Pharmacological blockade of RAGE or genetic deletion of RAGE imparts significant protection in murine models of diabetes, inflammatory conditions, Alzheimer’s disease, and tumors. Intriguingly, soluble forms of RAGE, including the splice variant–derived esRAGE, circulate in human plasma. Studies in human subjects suggest that sRAGE levels may be modulated by the diseases impacted by RAGE and its ligands. Thus, in addition to being a potential therapeutic target in chronic disease, monitoring of plasma sRAGE levels may provide a novel biomarker platform for tracking chronic inflammatory diseases, their severity, and response to therapeutic intervention.