TLR4 and Sepsis: During early sepsis, HMGB1 is released in the all-thiol fully reduced form.194 It forms heterocomplex with CXCL12 that binds to receptor CXCR4 to elicit chemotactic activity but not TLR4-dependent cytokine release.195 In this redox state, HMGB1 serve as endotoxin delivery protein that bind and internalizes LPS into lysosome, an intermediate step required for LPS cytosol release and activation of non-canonical caspase-11-dependent pyroptosis (Fig. 2).174