Editorial [ Receptor for Advanced Glycation Endproducts (RAGE): Coming Full Circle in Unraveling the Pathogenesis of Chronic Disease Guest Editor: Ann Marie Schmidt ]

In unraveling the biology of the Receptor for Advanced Glycation Endproducts (RAGE), it has become increasingly apparent that the ligands of RAGE stimulate signal transduction through this receptor - leading to cascades of events that, depending on the microenvironment, initiate and sustain chronic cell stress. In certain settings, however, RAGE-dependent signaling may augur repair and resolution of stress, especially where acute injury stimulates rapid generation and removal of RAGE ligands. Although first described as a receptor for the products of nonenzymatic glycation and oxidation of proteins, the Advanced Glycation Endproducts (AGEs) [1] the biology of RAGE blossomed upon the discovery that at least four other classes of molecules might bind this receptor. In addition to AGEs, RAGE binds S100/calgranulins, High Mobility Group-1, Mac-1, and amyloid-β peptide and β-sheet fibrils (Aβ) [2-5]. Together, these ligand families bespeak unifying mechanisms underlying the pathogenesis of chronic disease. Thus, irrespective of the specific etiology, the intriguing upregulation and accumulation of RAGE ligands in tissues beset by chronic disease brings RAGE squarely to the battlefield in disorders such as diabetes, chronic inflammation and autoimmunity, neurodegeneration, tumors and aging. As outlined in the reviews in this series, data in both cell culture and animal models of disease reveal significant protection from chronic injury in RAGE-modified mice, or in animals treated with antagonists of RAGE and its ligands. A key question has been asked many a time; how can this receptor be involved in such distinct settings of chronic stress? We propose that a common thread tying RAGE and its ligands to diverse disorders is the link to the inflammatory response. In each case, there is a plethora of evidence suggesting that monocytes, macrophages, T and B lymphocytes and in the central nervous system, glial cells, all of which express RAGE, contribute to tissue-perturbing signaling mechanisms that upregulate matrix metalloproteinases (MMPs), cytokines and other factors that damage tissue and suppress repair [6]. Further, earlier observations that many of RAGE's ligands, particularly the S100/calgranulins, were “biomarkers” of inflammation, ischemia/reperfusion stress and malignancy may now hold a mechanism-based context - we predict that autocrine and/or paracrine interactions of released RAGE ligands with RAGE-expressing cells amplify tissue stress and, if left unchecked, lead to chronic disease. Articles in this Review Series In this review series, we have gathered a compendium of reports that illustrate the evolving tale of RAGE. The first four articles focus on the discovery and implications of the ligand families of RAGE. Yan, Ramasamy and colleagues share insights on AGEs and RAGE, as well as other ligands, and how this interaction contributes importantly to diabetic complications in the cardiovascular system [7]. Donato provides a timely review on the key question - do all S100/calgranulins bind RAGE? In presenting the argument that the answer is probably “no”, Donato elucidates the effects of RAGE signaling stimulated by at least certain members of this family and their implications in inflammatory and neuronal stress [8]. Rauvala and Rouhaianen critically review what is currently known about HMGB1 and RAGE. In detailing the data indicating that RAGE is a signal transduction receptor for HMGB1, they present evidence on distinct receptors that may also engage this molecule [9]. Chen, Yan and colleagues reflect on the discovery that RAGE binds amyloid-β peptide and β-sheet fibrils. The implications of these species in neurodegeneration disorders such as Alzheimer's disease may reflect the tip of the iceberg in settings wherein such “tangled webs” may form, aggregate and emerge as new oligomeric structures highly capable of stimulating and signaling via RAGE [10]. Following these papers is a review on RAGE and its roles in the inflammatory response. Clynes, Schmidt and colleagues present the evidence - from delayed type hypersensitivity studies in non-diabetic mice - to T cell priming experiments in unique T cell receptor-modified mice and lymphocytes, that RAGE is essential for effective T cell priming in vivo [11]. These data provide definitive evidence linking RAGE to the adaptive immune response. The next articles focus on four specific areas in which RAGE and its ligands have been implicated using both cell culture and in vivo models. Yamamoto, Murakami and colleagues review key studies linking RAGE to diabetic nephropathy wherein experiments using RAGE-modified mice clearly reveal that RAGE is essential for the development and progression of this disorder [12]. Barile and Schmidt review the state of RAGE in diabetic and aginglinked retinopathies [13], and Toth, Martinez and Zochodne review the state of RAGE in diabetic neuropathy [14]. In retinopathy and neuropathy, animal models of diabetes revealed striking upregulation of RAGE in these affected tissues, and that pharmacological and/or genetic deletion of RAGE provided protection against the functional and pathological indices of these two disorders. Lastly, Logsdon, Arumugam and colleagues review the biology of RAGE and its ligands in cancer. Far from being “innocent bystanders” and biomarkers in cancer, evidence is mounting that RAGE may be important in mechanisms linked to tumor growth and metastases [15]. Fascinating questions arise in cancer in the context of tumor and/or host roles for this receptor as detailed by these authors. RAGE & Human Biology RAGE blockade is the subject of ongoing clinical trials, thus, there are no data at this time revealing “efficacy” of targeting this approach in human subjects with chronic diseases. It is too soon. Yet, studies in cells and animals continue to deeply probe the questions of “natural” roles for RAGE. Indeed, we speculate that analogous mechanisms linking RAGE to injury may be evolutionarily conserved pathways that in simpler systems, evoked repair. Is there evidence, though, suggesting links between RAGE and human disease? The answer is an emphatic “yes!” Two major areas of research are ongoing probing these exact concepts. First, “soluble” forms of RAGE have been detected in the plasma of human subjects. Apparently produced by alternative splicing programs yielding “endogenous secretory” or esRAGE, these circulating levels of RAGE appear to be associated with disease states, and perhaps may be mutable in response to therapeutic interventions (recently reviewed in [16]). Second, polymorphisms of RAGE have been uncovered that may, especially upon study in large scale observational trials, shed light on vulnerability to development of chronic diseases such as diabetic complications, neurodegeneration or to autoimmune disorders, and/or to the severity of chronic disease states [17]. Published information on RAGE polymorphisms and cardiovascular disease is presented in the review by Yan and Ramasamy [7]. Perspective Taken together, evidence presented herein links RAGE to the pathogenesis of an array of chronic disease states characterized by upregulation and accumulation of RAGE ligands. Far from reflecting “one ligand - one disease,” emerging evidence points to the family of RAGE ligands as key players in the steps launching and perpetuating chronic disease and tissue damage. Drawing the fine line between injury and repair in the biology of RAGE is an important challenge but one well worth the effort of in-depth and hypothesis-driven experimentation. We predict that solving this puzzle may lead to effective therapies for chronic diseases such as inflammation and autoimmunity, neuronal degeneration, unchecked cellular proliferation and metastasis, and AGEing. ACKNOWLEDGEMENTS Thank you to all the authors and peer reviewers who contributed to the development and refinement of this review series on RAGE. Together, we thank the editors of Current Molecular Medicine for the gracious invitation to prepare this series on RAGE, the molecule to which our lives are dedicated! 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