Th e signaling cascade(s) of RAGE -induced by engagement of its various ligands -that ultimately activates NF-κB is largely unknown. Th e predicted cytosolic portion of RAGE, consisting of 43 amino acids, is short compared to other PRRs, the TLRs and IL-1 receptors, and does not include a known signaling domain or motif. A RAGE mutant lacking this intracellular tail does not activate NF-κB and behaves like a dominant negative, preventing proinfl ammatory cytokine release from macro phages. Th ese data indicate a critical role of this cytosolic portion in transducing the signal from the cell surface to the nucleus. The damage-associated molecular patterns (DAMPs), high-mobility group box 1 (HMGB1) and S100A12, are released during infection ( [15, 17] , and unpublished data) and bind to and activate RAGE. It has to be determined whether other S100 proteins and other DAMPs are RAGE ligands (indicated as purple shapes) released during infection. It would be interesting to investigate whether RAGE can directly bind to, become activated and mount a fi rst immune reaction after ligation with specifi c PAMPs as well. Engagement of RAGE by its ligands results in receptor-dependent signaling and activation of NF-κB leading to a pro-infl ammatory response; the signaling pathway is largely unknown. In addition, RAGE interacts as an endothelial (and epithelial) adhesion receptor with the leukocyte integrin, CD11b/CD18 (Mac-1) (lower section) [8] . Furthermore, lateral (in cis) RAGE-Mac-1 interaction on the leukocyte surface is mediated by HMGB1 and activates Mac-1-intercellular adhesion molecule (ICAM)-1 dependent adhesion and migration and augments leukocyte recruitment [27] (indicated by the blue line and blue "+"). Moreover, a recent report shows that endothelially expressed RAGE acts in concert with ICAM-1 in mediating β 2 integrin-dependent leukocyte adhesion during acute trauma-induced infl ammation [28] (indicated by the green line and green "+"). One possibility is that RAGE uses as yet unknown adaptors framing a whole `new' signaling cascade to NF-κB. Another possibility is that the RAGE tail interacts with a Toll/IL-1 receptor (TIR)-containing protein which then recruits the downstream TIR-contain ing proteins in a way analogous to TLR-mediated signaling pathways. Finally, RAGE could transduce signals from the cell surface to the nucleus by bypassing the TIR-containing adaptor, directly interacting with member(s) of the signaling cascade.