In the same surgically (CLP)-induced model of sepsis, RAGE defi ciency and anti-RAGE therapy were reported not to aff ect bacterial outgrowth in the peritoneum, liver, or spleen [41] . Notwithstanding, a possible role of RAGE in antibacterial defense cannot be easily evaluated from this study because host defense against CLP depends, at least in part, on the extent of intestinal necrosis and the formation of a local abscess. Also, all mice in this experiment received broad spectrum antibiotics and bacterial outgrowth was only determined in mice that survived (i.e., not at predefi ned time points after CLP). For this reason, we used our model of abdominal sepsis induced by injection of the Gram-negative bacterium Escherichia coli into the peritoneum [42, 43] to study whether RAGE aff ects antibacterial defense. Th is model is a relevant tool to investigate the role of receptors/ mediators in limiting the growth and dissemination of bacteria after a primary intra-abdominal infection and to assess the contribution of these proteins to specifi c immune responses. RAGE expression was upregulated during E. coli induced sepsis [42] . RAGE defi ciency (either pharmacologically using anti-RAGE IgG antibodies or genetically using RAGE knock out mice) was related to a higher bacterial load and dissemination [42] . Th ese data indicate that RAGE signaling contributes to an eff ective antibacterial response during abdominal sepsis. RAGE exerted this eff ect probably indirectly and not via direct interaction with E. coli, considering the observation that leukocytes from RAGE -/mice had an unaltered capacity to phagocytose and kill E. coli in vitro. Furthermore, the fi nding that defi ciency of RAGE in general was associated with an exaggerated host response during E. coli sepsis [42] on the one hand, and with an attenuated infl ammatory response and better survival in (other) sterile models of intraperitoneal injection of LPS derived from E. coli [42, 44] on the other hand, suggests that although RAGE is involved in the immune reaction to E. coli, this function can be compensated for by other receptors in the presence of a growing bacterial load. Th e high-affi nity RAGE ligand, HMGB1, is secreted into the circulation systemically during clinical sepsis [16] [17] [18] as well as in our experimental sepsis model of E. coli [43] . Importantly, HMGB1 has been shown to transduce cellular signals in vitro and in vivo by interacting with at least three other receptors, i.e., TLR2, TLR4 and TLR9 when HMGB1 is complexed with CPG DNA [24, 44, 45] . One possible explanation for the increased response in the RAGE lacking mice during E. coli sepsis is, therefore, that the absence of RAGE could facilitate the interaction between HMGB1 and TLR2, TLR4 and/or TLR9.