As noted above, PRRs are a group of molecules that recognize the molecular patterns of DAMPs. These receptors may be activated by PAMPs, alarmins, or both, to activate the immune system. Several important receptors have been implicated in HMGB1 signaling, including the receptor for advanced glycation end products (RAGE) and members of the Toll-like family of receptors (TLRs). RAGE is a transmembrane protein expressed at low levels in normal tissues that is upregulated at sites where its ligands accumulate (46) . The receptor first was identified to bind advanced glycation end products in diabetes, but has since been identified to bind other ligands and is involved in multiple inflammatory states (46, 47) . RAGE was also the first receptor demonstrated to bind HMGB1 (48) . At the time, the consequences of HMGB1 interaction with RAGE were unknown, but it was discovered later that HMGB-1 signaling through RAGE promotes chemotaxis and the production of cytokines in a process that involves the activation of the transcription factor nuclear factor-κB (NF-κB) (49, 50) . Other RAGE-dependent effects of HMGB1 appear to involve the maturation (23, (51) (52) (53) and migration (38, (53) (54) (55) (56) of immune cells as well as the upregulation of cell surface receptors (57) (58) (59) .