Taming the RAGE of Inflammation

Hofmann MA, Drury S, Fu C, et al. RAGE Mediates a Novel Proinflammatory Axis: A Central Cell Surface Receptor for S100/Calgranulin Polypeptides. Cell 1999;97:889–901. Summary: Hofmann et al. delineate the receptor for advanced glycation end products (RAGE) as a signal transduction receptor in a key proinflammatory pathway. In this study, a 12-kDa peptide with RAGE-binding properties, termed extracellular newly identified RAGE-binding protein (EN-RAGE), was identified in bovine lung extracts. EN-RAGE bears homologies to other members of the S100/calgranulin polypeptide family. Radioligand binding studies have demonstrated specific interactions between RAGE and EN-RAGE that were inhibited in the presence of either a soluble form of RAGE (sRAGE) or antibodies directed toward either RAGE or EN-RAGE (Fig. 1). The absence of the cytoplasmic tail of RAGE was also shown to abrogate responses mediated by EN-RAGE/RAGE binding.FIG. 1.: Model of EN-RAGE/RAGE binding and potential sites of interruption of binding. Binding of extracellular EN-RAGE with trans-membrane receptor RAGE induces signal transduction events mediated by nuclear factor (NF)-κB leading to induction of proinflammatory peptides including tumor necrosis factor-α. Antibodies to both EN-RAGE and RAGE, as well as soluble RAGE (sRAGE) interrupt binding of EN-RAGE to RAGE. In addition, signaling through RAGE is prevented if the cytoplasmic tail of RAGE is absent (not depicted).Expression of EN-RAGE was upregulated in Jurkat T cells but not endothelial cells exposed to tumor necrosis factor (TNF)-α. In addition, when mice were exposed to lipopolysaccharide, a time-dependent elevation in plasma EN-RAGE was detected. The role of EN-RAGE in vitro was delineated in endothelial and mononuclear cells. EN-RAGE exhibited chemoattractant properties and mitogenic activity and induced specific cell cytokine responses in association with activation of nuclear factor (NF)-κB. Inhibition of these effects by multiple modalities abrogated the effects of EN-RAGE. In vivo experiments confirmed the role of this ligand–receptor interaction in mediating inflammation. Several murine models of inflammation were used, each of which demonstrated that inflammation was abrogated by inhibition of EN-RAGE/RAGE interactions. Of particular interest, the interleukin (IL)-10 knockout murine model of colitis was used. In comparison with control IL-10–deficient mice, inhibition of EN-RAGE binding to RAGE by sRAGE decreased colonic inflammation, reduced NF-κB nuclear translocation and suppressed TNF-α secretion. Comment: Proteins belonging to the S100 family, characterized by the presence of two calcium-binding sites, are expressed by granulocytes and monocytes. A hallmark of these polypeptides is accumulation during chronic inflammatory processes including inflammatory bowel disease (IBD) (Digestion 1997;58:176–80). Levels of S100 proteins correlate with disease activity when measured in both serum (Eur J Clin Invest 1995;25:659–64) and stool (Scand J Gastroenterol 1999;34:50–4) obtained from patients with Crohn's disease and ulcerative colitis. What has not been fully evident to date is how members of the S100 family mediate inflammation. Hofmann et al. begin to answer this question by identifying the interaction between EN-RAGE and other members of the S100 family and the cell surface receptor RAGE. RAGE is expressed widely in various tissues, including endothelial cells, and was named for its ability to bind advanced glycation end products (AGE) (J Biol Chem 1992;267:14998–5004). AGEs result from nonenzymatic glycation of proteins and lipids and accumulate during normal aging. They accumulate at accelerated rates in diabetes and are implicated in the pathogenesis of diabetic vasculopathy (J Clin Invest 1996;98:1088–94). In addition, amphoterin (associated with neurite outgrowth) (J Biol Chem 1995;270:25752–761) and amyloid β-peptide (implicated in the pathogenesis of Alzheimer's disease) (Nature 1996;382:685–91) also bind to RAGE. The newly described binding of two members of the S100 family of peptides to RAGE suggests an additional role for this receptor. EN-RAGE expression is upregulated following activation of mononuclear cells and lymphocytes. Consistent with the premise that S100 proteins are derived from inflammatory cells, endothelial cells did not express EN-RAGE. Unfortunately, the role of EN-RAGE expression in neutrophils and epithelial cells was not determined in the current study. Given the role of neutrophils in acute inflammation, these inflammatory cells also would be expected to express EN-RAGE. In addition, current evidence indicates that epithelial cells have important roles in mediating inflammation (Gastroenterology 1999;117:359–67;Gastroenterology 1997;113:1214–23). Therefore, the investigation of EN-RAGE in this cell type is of interest. The specificity of increased EN-RAGE expression after activation of inflammatory cells remains unclear. In the current study two modes of stimulation were used: cross-linking of CD3/CD28 for mononuclear cells and lymphocytes and systemically administered lipopolysaccharide. The effect of other stimulatory agents, such as proinflammatory chemokines or pathogen-derived components, requires further investigation. This is particularly relevant in determining whether EN-RAGE and related peptides have effects as primary determinants of chronic inflammation and/or as secondary mediators leading to perpetuation of inflammation. The in vivo experiments reported by Hofmann et al. define additional aspects of interactions between EN-RAGE and RAGE. The role of EN-RAGE in several distinct inflammatory models was delineated by blocking interactions with RAGE. The consequence of local (foot-pad) and systemic administration of EN-RAGE, simulating inflammation and release of peptides from inflammatory cells, resulted in activation and migration of inflammatory cells. Additionally, challenge of mice with CP-10, another member of the S100 family, leads to enhanced chemotaxis and increased phagocytosis (Biochim Biophys Acta 1996;1313:246–52). The IL-10 knockout model of colitis in mice could be used to further define the effects of EN-RAGE administration. Raising IL-10–deficient mice in pathogen-free conditions delays the development of colitis in comparison with similar mice raised under standard environmental conditions (Cell 1993;75:263–74). Pathogen-free IL-10–deficient mice challenged with EN-RAGE may then have colitis develop in a manner similar to control mice. Hofmann et al. demonstrate that intracellular signal transduction pathways are induced after binding of EN-RAGE to RAGE with activation of NF-κB shown by electrophoretic mobility shift assay. NF-κB activation is associated with increased transcription of many inflammatory proteins including cell adhesion molecules, interleukins, and growth factors (Gut 1998;43:856–60). In this study, the consequences of NF-κB induction were shown in vitro by enhanced expression of cell adhesion molecules. In vivo, prevention of NF-κB signaling by interruption of EN-RAGE/RAGE binding resulted in diminished TNF-α production (compared with that in control animals). Whether EN-RAGE/RAGE–mediated activation of NF-κB also leads to induction of other peptides remains to be determined. In addition to NF-κB activation, binding of AGE proteins to RAGE also activates a second pathway involving the small G-protein Ras and the transcription factor AP-1 (FEBS Lett 1997;410:481–4). Therefore, additional signal transduction pathways may be activated after interactions between EN-RAGE and RAGE. Further study of the signaling cascades consequent to EN-RAGE/RAGE binding is necessary to fully understand the role of this ligand in inflammation. The data presented by Hofmann et al. suggest that intervention in the interaction between EN-RAGE and RAGE could have therapeutic promise for chronic inflammatory states such as IBD. Although suppression of host immune responses is a cornerstone to treatment of IBD, current therapeutic agents are far from ideal, because of absence of response and undesired side effects. Recently, the advent of anti-TNF-α therapy targeting TNF-α, a key proinflammatory cytokine, has shown the benefits of interruption of this inflammatory cascade in Crohn's disease (Gastroenterology 1999;116:1029–34). The advantage of considering inhibition of EN-RAGE/RAGE interactions is that these events occur proximal to TNF-α and other proinflammatory peptides mediated by NF-κB. This should enable more effective abrogation of inflammation. Therapy using sRAGE may prove to be beneficial for other inflammatory and disease states associated with RAGE. For example, administration of sRAGE results in suppression of diabetic atherosclerosis in a mouse model (Nat Med 1998;4:1025–31). Thus, Hofmann et al. have reported important advances in understanding of inflammatory processes. In addition, these findings hint at prospects of future potential therapeutic options in the management of chronic inflammatory states, including IBD.

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