CommentarySoluble RAGE: Therapy and biomarker in unraveling the RAGE axis in chronic disease and aging
Graphical abstract
Introduction
The Receptor for Advanced Glycation Endproducts (RAGE) is a ubiquitous receptor present on epithelial, neuronal, vascular and inflammatory cells, usually expressed at low levels in homeostasis and to increased degrees at sites of stress or injury [1]. A notable exception is the lung, in which relatively high basal levels of RAGE expression have been identified relative to other tissues [2].
The multi-ligand nature of RAGE places this receptor in the midst of chronic disease states, such as diabetes, aging, inflammation, neurodegeneration, amyloidoses, and tumors. Experimental evidence using pharmacological antagonists of RAGE and genetically modified mice suggests that blocking RAGE halts progression of chronic inflammation and cell stress. In animal models, administration of the ligand-binding extracellular domain of RAGE, soluble RAGE, suppresses immediate and chronic inflammatory stresses thereby thwarting tissue injury [1].
Although there is one gene encoding RAGE, AGER[2], it is now clear that in human and murine systems, multiple splice variants of this gene may be detected. One such variant in the human subject encodes for “endogenous secretory (es) RAGE,” also known as RAGE_v1 according to the Human Gene Nomenclature Committee, a naturally occurring soluble form of the receptor lacking the membrane and intracellular domains [3], [4]. Although forms of soluble RAGE are readily detected and quantified in human plasma/serum by ELISA, detectable amounts of soluble RAGE have not been identified to date in the murine circulation [5]. In human subjects, studies suggest that the absolute levels of soluble RAGE may correlate with chronic disease states and their severity, and that soluble RAGE levels may be mutable consequent to therapeutic interventions [6].
In this review, we will discuss the state of RAGE, soluble RAGE and implications for the therapy and biomarking of chronic diseases and innate aging.
Section snippets
RAGE: extracellular domain and ligand binding
RAGE is a member of the immunoglobulin superfamily. The extracellular domain of RAGE is composed of one variable (V)-type immunoglobulin (Ig) domain followed by two distinct constant (C)-type domains [2]. Recent evidence deduced from various biochemical techniques suggests that the V and C1 RAGE domains are not independent of each other but that they form an integrated structural unit required for at least some of the ligand binding properties [7]. Further, it was suggested by that work that
RAGE: intracellular domain and signal transduction
The cytoplasmic domain of RAGE is linked to the extracellular domain by a single transmembrane domain. The intracellular domain is short (<50 amino acids) and highly charged [2]. Studies in cultured cells and in vivo using tissue-targeted transgenic mice reveal that the cytoplasmic domain of RAGE is essential for RAGE ligand-triggered signal transduction, as deletion of the cytoplasmic domain of RAGE blocks ligands from inducing signaling and modulating gene expression. However, exposure of
Soluble RAGE: pharmacology and findings in animal models
The soluble extracellular domain of RAGE has been prepared for experimentation in in vitro and in vivo model systems. In vitro, soluble RAGE added to cultured cells blocked the effects of RAGE ligands on expression of inflammatory markers, cellular migration and proliferation, and cytotoxicity [23], [26], [27], [28]. These promising studies set the stage for rigorous testing of these concepts in vivo. Thus, the key test of the ligand decoy capacities of soluble RAGE was established in animal
Soluble RAGE in human circulation – mediator or biomarker or both?
As discussed above, there are two known forms of soluble RAGE in human plasma; the first is generated from the actions of ADAM10 (A Disintegrin And Metallopeptidase 10) and MMPs presumably on cell surface RAGE [67], [68], and the second is an alternatively spliced pre-mRNA form of the receptor known as endogenous secretory or esRAGE (or RAGE_v1) [3], [4] (Fig. 2). The latter contains a novel stretch of amino acids in the C2-Ig domain, thereby presenting a unique sequence for the generation of
Summary
Recent insights into the precise nature of RAGE ligands and their interaction with RAGE V-, C1, and/or C2 domains have suggested mechanisms by which the diverse ligands of RAGE may exert distinct responses in signal transduction and response to stress. In vivo, however, the concept of “one ligand-one disease” is not likely to be realistic, as we propose that in diabetes, for example, although elevated levels of glucose may trigger rapid development of AGEs, the consequent inflammatory response
Acknowledgements
This work was funded by grants from the United States Public Health Service and the Juvenile Diabetes Research Foundation.
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