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Published online before print May 18, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1206751

Received for publication December 22, 2006.
Revised April 14, 2007.
Accepted for publication April 17, 2007.

Article

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

Kevan Herold ^*, Bernhard Moser , Yali Chen , Shan Zeng , Shi Fang Yan , Ravichandran Ramasamy , Jean Emond , Raphael Clynes , and Ann Marie Schmidt ^@

*Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Surgery and Medicine, Columbia University Medical Center, New York, New York, USA

^@ To whom correspondence should be addressed. E-mail: ams11{at}columbia.edu.

	Abstract

The multiligand receptor for advanced glycation end products (RAGE) of the Ig superfamily transduces the biological impact of discrete families of ligands, including advanced glycation end products, certain members of the S100/calgranulin family, high mobility group box-1, membrane-activated complex-1, and amyloid- peptide and -sheet fibrils. Although structurally dissimilar, at least at the monomeric level, recent evidence suggests that oligomeric forms of these RAGE ligands may be especially apt to activate the receptor and up-regulate a program of inflammatory and tissue injury-provoking genes. The challenge in probing the biology of RAGE and its impact 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 environments laden with oxidative stress, inflammation, innate aging, or high glucose, as examples, the function of these ligand families may be transformed 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 delineating optimal strategies to target RAGE in the clinic.

Key Words: inflammation • immunity

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