The importance of HMGB1 signaling through TLR4 in hepatic IRI was further clarified in subsequent in vivo experiments by the generation of chimeric mice in which TLR4-derived bone marrow cells were shown to be largely responsible for the initiation and propagation of the inflammatory response. In this set of experiments, mice expressing TLR4 mutant bone marrow-derived cells were protected from liver damage as compared to those expressing TLR4 wild type bone marrow-derived cells. This occurred independently of the TLR4 phenotype expressed on hepatocytes (119). Subsequently, it was shown that increasing the number of hepatic dendritic cells worsened liver damage in TLR4 wildtype but not TLR4 mutant animals (59) , thus suggesting that dendritic cells are involved in the recognition of and response to DAMPs (HMGB1 included) released after acute injury in this model. The molecular mechanisms of HMGB1/ TLR4-dependent IRI involve the production of reactive oxygen species in a process that appears to be dependent on calcium signaling via the calcium/ calmodulin-dependent kinases (CaMK) whose activation is ultimately involved in the release of HMGB1 (43) .