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Review
. 2001 Oct;108(7):949-55.
doi: 10.1172/JCI14002.

The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses

A M Schmidt  1 , S D Yan, S F Yan, D M Stern
Affiliations
Review

The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses

A M Schmidt et al. J Clin Invest. 2001 Oct.
No abstract available

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Figures

Figure 1
Figure 1
Schematic depiction of RAGE-ligand interaction showing domains of the receptor. The V-type domain is critical for binding of RAGE ligands. Deletion of the cytosolic tail results in a modified form of RAGE that binds ligands, remains firmly embedded in the cell membrane, but does not transmit RAGE-mediated cellular activation. Even in the presence of endogenous full-length RAGE, expression of dominant negative RAGE blocks signaling from the receptor. sRAGE, soluble RAGE (extracellular domain of RAGE); DN-RAGE, dominant negative RAGE (extracellular domain + transmembrane-spanning domain).
Figure 2
Figure 2
Schematic depiction of a two-hit model of vascular perturbation mediated by RAGE and its ligands. We hypothesize that the diabetic vessel wall displays increased expression of RAGE ligands and the receptor itself (first hit). In the presence of additional perturbation (second hit), such as ischemic stress, immune/inflammatory stimuli, physical stress, or modified lipoproteins, there is an exaggerated cellular response promoting formation of vascular lesions (rather than restitution of vascular homeostasis).
Figure 3
Figure 3
Schematic depiction of a role for receptor-mediated interaction with pathogenic Aβ assemblies (which could be dimers, multimers, and/or fibrils) in mediating cellular dysfunction early in amyloidoses (left). In contrast, nonspecific neuronal/cellular toxicity (for example, interfering with the integrity of cell membranes) is likely to be an important mechanism of cellular injury at later stages of the disease when there is a higher level of Aβ (right).
Figure 4
Figure 4
Schematic depiction of a role for RAGE and its ligands (especially S100/calgranulins) at the site of a chronic immune/inflammatory response. We hypothesize that S100/calgranulin-RAGE interaction provides a mechanism amplifying the inflammatory response by mediating activation of RAGE-bearing cells, including mononuclear phagocytes, lymphocytes, and cells in the vessel wall. In contrast, RAGE and its ligands are not the trigger for initiating the host response, which may be due to primary immune, inflammatory, or infectious stimuli.
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