Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress

The multiligand receptor for advanced glycation end products (RAGE) of the Ig superfam- ily transduces the biological impact of discrete families of ligands, including advanced glycation end products, certain members of the S100/cal- granulin family, high mobility group box-1, mem- brane-activated complex-1, and amyloid- peptide and -sheet fibrils. Although structurally dissimi- lar, at least at the monomeric level, recent evi- dence suggests that oligomeric forms of these RAGE ligands may be especially apt to activate the receptor and up-regulate a program of inflamma- tory and tissue injury-provoking genes. The chal- lenge in probing the biology of RAGE and its im- pact in acute responses to stress and the potential development of chronic disease are to draw the line between mechanisms that evoke repair versus those that sustain inflammation and tissue damage. In this review, we suggest the concept that the ligands of RAGE comprise a primal program in the acute response to stress. When up-regulated in en- vironments laden with oxidative stress, inflamma- tion, innate aging, or high glucose, as examples, the function of these ligand families may be trans- formed from ones linked to rapid repair to those that drive chronic disease. Identification of the threshold beyond which ligands of RAGE mediate repair versus injury is a central component in de- lineating optimal strategies to target RAGE in the clinic. J. Leukoc. Biol. 82: 000-000; 2007.