Levels of the high-affi nity RAGE ligand, HMGB1, were higher in BAL fl uid from patients with pneumonia compared to BAL fl uid from healthy controls [17] . In experimentally induced pneumococcal pneumonia, the presence of RAGE was detrimental: Mice lacking RAGE had a better survival rate together with a lower pulmonary bacterial load and decreased dissemination of S. pneumoniae to blood and spleen compared to wildtype mice [39] . Th e diff erence was possibly partially due to an increased killing capacity of RAGE -/alveolar macrophages. Additionally, lung injury and neutrophil recruitment were reduced in the RAGE -/mice, which parallels fi ndings on RAGE as an endothelial counter receptor for the β2 integrin, Mac-1, [8] and the interplay between RAGE and Mac-1 on leukocytes, required for HMGB1-mediated infl ammatory cell recruitment [27] . In addition, blockade of the RAGE-HMGB1 interaction and prevention of the subsequent pro-infl ammatory stimulus might be an explanation for the less severe pulmonary damage in the RAGE -/mice during S. pneumoniae pneumonia.