An 8-Hydroxy-Quinoline Derivative Protects Against Lipopolysaccharide-Induced Lethality in Endotoxemia by Inhibiting HMGB1-Mediated Caspase-11 Signaling

Xiangyu Wang; Jian Shi; Zhaozheng Li; Ling Li; Rui Zhang; Yang Bai; Junmei Li; Fang Liang; Yiting Tang

doi:10.3389/fphar.2021.673818

An 8-Hydroxy-Quinoline Derivative Protects Against Lipopolysaccharide-Induced Lethality in Endotoxemia by Inhibiting HMGB1-Mediated Caspase-11 Signaling

Front Pharmacol. 2021 May 21:12:673818. doi: 10.3389/fphar.2021.673818. eCollection 2021.

Authors

Xiangyu Wang^{1

2}, Jian Shi³, Zhaozheng Li², Ling Li², Rui Zhang², Yang Bai², Junmei Li², Fang Liang², Yiting Tang^{1

2}

Affiliations

¹ Department of Physiology, School of Basic Medical Science, Central South University, Changsha, China.
² Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
³ Department of Spine Surgury, The Third Xiangya Hospital, Central South University, Changsha, China.

Abstract

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-1α and IL-1β 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.

Keywords: HMGB1; caspase-11; inflammasome; phenotypic screening; pyroptosis; sepsis.