Author: Schmidt, Ann M.

Source: Current Molecular Medicine, Volume 7, Number 8, December 2007 , pp. 697-698(2)

Publisher: Bentham Science Publishers

Abstract:

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.

Document Type: Research article

DOI: http://dx.doi.org/10.2174/156652407783220723

Publication date: 2007-12-01

More about this publication?

• Current Molecular Medicine is an interdisciplinary journal focused on providing the readership with current and comprehensive reviews on fundamental molecular mechanisms of disease pathogenesis, the development of molecular-diagnosis and/or novel approaches to rational treatment. The reviews should be of significant interest to basic researchers and clinical investigators in molecular medicine. Periodically the journal will invite guest editors to devote an issue on a basic research area that shows promise to advance our understanding of the molecular mechanism(s) of a disease or has potential for clinical applications.

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