Fig. 8

Molecules inhibiting RAGE-mediated endocytosis of LPS-HMGB1 complexes. The pathogenesis of endotoxemia is caused by extracellular LPS getting attaching to extracellular HMGB1 and forming a complex that is endocytosed via RAGE-dependent pathway. Both LPS and HMGB1 then activate endosomal TLR4 receptors before being transferred to the lysosomal system. HMGB1 permeabilizes lysosomal membranes under acidic conditions and thus allows LPS to avoid lysosomal degradation and leaks out into the cytosol (Deng et al. 2018a). LPS is thus enabled to activate its key cytosolic receptor, caspase-11 in murine macrophages to induce pyroptosis. The discoveries of the present study are that box A, anti-HMGB1 m2G7 and acetylcholine each inhibits the cellular internalization of LPS-HMGB1 complexes and subsequent immune activation