An 8-Hydroxy-Quinoline Derivative Protects Against Lipopolysaccharide-Induced Lethality In Endotoxemia By Inhibiting Hmgb1-Mediated Caspase-11 Signaling

Sepsis, an inflammatory syndrome secondary to infection, is the leading cause of in-hospital lethality. It is evidenced that LPS, the major pathological component of the Gram-negative bacteria membrane, predominantly contributes to the pathogenesis of sepsis. Cytoplasmic lipopolysaccharide (LPS) can be sensed by the noncanonical inflammasome and triggers the oligomerization of caspase-11, resulting in pyroptosis and lethal immune responses in sepsis. A previous study has shown that hepatocyte-released high mobility group box 1 (HMGB1) mediates caspase-11-dependent lethality in sepsis by delivering extracellular LPS into the cytosol. Here, we established a phenotypic screening system using recombinant HMGB1 plus LPS in mouse peritoneal macrophages, identifying a novel 8-hydroxyquinoline derivative named 7-[phenyl (pyridin-2-ylamino) methyl] quinolin-8-ol (8-ol, NSC84094) that can specifically inhibit HMGB1-mediated caspase-11 signaling. 8-ol targets directly to HMGB1 and changes the secondary conformation, consequently disrupting the interaction between LPS and HMGB1 and inhibiting the HMGB1-mediated delivery of LPS into the cytosol. Intervention of 8-ol significantly reduced the release of IL-1 alpha and IL-1 beta and protected against caspase-11-mediated organ injury and lethality in endotoxemic mice. Thus, this study clearly suggests that the HMGB1-caspase-11 pathway is a potential drug target in lethal immune disorders and might open a new avenue in the treatment of sepsis.