Active release of HMGB1 from hepatocytes were identified as the major source of pro-inflammatory systemic HMGB1 in endotoxemia and CLP sepsis.174 The translocation of HMGB1 required co-activation of both TLR4 and caspase11/GSDMD signaling (Fig. 2).188 In line, increased TLR4 activation and intracellular uptake of LPS induce GSDMD cleavage via direct activation of caspase-11 found in cytosolic compartment of macrophages. Here, GSDMD is linked to serum lipopolysaccharide activity.