Figure 4.

LPS needs HMGB1 to trigger severe inflammation. Injected LPS and type 1 interferon, (which generates HMGB1 release) in TLR4 gene-deficient mice is lethal in contrast to when administered to caspase-11 knockout mice [75,76]. The initial event in LPS toxicity is due to extracellular LPS activation of cell surface TLR4, which triggers extracellular HMGB1 release. HMGB1 has two LPS-binding sites (Figure 1) and thus forms extracellular HMGB1-LPS complexes that get endocytosed via RAGE to finally reach the cytosol culminating in caspase-11 activation (in mice; caspases 4/5 in humans) causing inflammation and coagulation.