The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis

Meihong Deng; Yiting Tang; Wenbo Li; Xiangyu Wang; Rui Zhang; Xianying Zhang; Xin Zhao; Jian Liu; Cheng Tang; Zhonghua Liu; Yongzhuo Huang; Huige Peng; Lehui Xiao; Daolin Tang; Melanie J Scott; Qingde Wang; Jing Liu; Xianzhong Xiao; Simon Watkins; Jianhua Li; Huan Yang; Haichao Wang; Fangping Chen; Kevin J Tracey; Timothy R Billiar; Ben Lu

doi:10.1016/j.immuni.2018.08.016

The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis

Immunity. 2018 Oct 16;49(4):740-753.e7. doi: 10.1016/j.immuni.2018.08.016. Epub 2018 Oct 9.

Authors

Meihong Deng¹, Yiting Tang², Wenbo Li³, Xiangyu Wang⁴, Rui Zhang⁴, Xianying Zhang⁴, Xin Zhao⁴, Jian Liu⁴, Cheng Tang⁵, Zhonghua Liu⁵, Yongzhuo Huang⁶, Huige Peng⁶, Lehui Xiao⁷, Daolin Tang¹, Melanie J Scott¹, Qingde Wang¹, Jing Liu⁸, Xianzhong Xiao⁹, Simon Watkins¹⁰, Jianhua Li¹¹, Huan Yang¹¹, Haichao Wang¹², Fangping Chen⁸, Kevin J Tracey¹¹, Timothy R Billiar¹³, Ben Lu¹⁴

Affiliations

¹ Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
² Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province 410000, P.R. China.
³ Department of Hematology and Key Laboratory of Non-resolving Inflammation and Cancer of Hunan Province, The 3rd Xiangya Hospital, Central South University, Changsha 410000, P.R. China; Key Laboratory of Medical Genetics, School of Biological Science and Technology, Central South University, Changsha, Hunan Province 410000, P.R. China.
⁴ Department of Hematology and Key Laboratory of Non-resolving Inflammation and Cancer of Hunan Province, The 3rd Xiangya Hospital, Central South University, Changsha 410000, P.R. China; Key Laboratory of Medical Genetics, School of Biological Science and Technology, Central South University, Changsha, Hunan Province 410000, P.R. China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan Province 410000, P.R. China.
⁵ College of Life Science, Hunan Normal University, Changsha 410081, P.R. China.
⁶ Shanghai Institute of Materia Medica, Chinese Academy of Science, 501 Hai-ke Rd, Shanghai 201203, P.R. China.
⁷ College of Chemistry, Nankai University, Tianjin 300073, P.R. China.
⁸ Department of Hematology and Key Laboratory of Non-resolving Inflammation and Cancer of Hunan Province, The 3rd Xiangya Hospital, Central South University, Changsha 410000, P.R. China.
⁹ Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan Province 410000, P.R. China.
¹⁰ Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
¹¹ Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.
¹² Department of Emergency Medicine, North Shore University Hospital, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.
¹³ Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: billiartr@upmc.edu.
¹⁴ Department of Hematology and Key Laboratory of Non-resolving Inflammation and Cancer of Hunan Province, The 3rd Xiangya Hospital, Central South University, Changsha 410000, P.R. China; Key Laboratory of Medical Genetics, School of Biological Science and Technology, Central South University, Changsha, Hunan Province 410000, P.R. China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan Province 410000, P.R. China. Electronic address: xybenlu@csu.edu.cn.

Abstract

Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, a lytic form of cell death. Caspase-11-dependent pyroptosis mediates lethality in endotoxemia, but it is unclear how LPS is delivered into the cytosol for the activation of caspase-11. Here we discovered that hepatocyte-released high mobility group box 1 (HMGB1) was required for caspase-11-dependent pyroptosis and lethality in endotoxemia and bacterial sepsis. Mechanistically, hepatocyte-released HMGB1 bound LPS and targeted its internalization into the lysosomes of macrophages and endothelial cells via the receptor for advanced glycation end-products (RAGE). Subsequently, HMGB1 permeabilized the phospholipid bilayer in the acidic environment of lysosomes. This resulted in LPS leakage into the cytosol and caspase-11 activation. Depletion of hepatocyte HMGB1, inhibition of hepatocyte HMGB1 release, neutralizing extracellular HMGB1, or RAGE deficiency prevented caspase-11-dependent pyroptosis and death in endotoxemia and bacterial sepsis. These findings indicate that HMGB1 interacts with LPS to mediate caspase-11-dependent pyroptosis in lethal sepsis.

Keywords: HMGB1; caspase-11; endotoxemia; inflammasome; pyroptosis; sepsis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caspases / genetics
Caspases / immunology*
Caspases / metabolism
Cells, Cultured
Endothelial Cells / immunology
Endothelial Cells / metabolism
Endotoxins / immunology*
Endotoxins / metabolism
HEK293 Cells
HMGB1 Protein / genetics
HMGB1 Protein / immunology*
HMGB1 Protein / metabolism
Humans
Lipopolysaccharides / immunology
Lipopolysaccharides / metabolism
Macrophages / immunology
Macrophages / metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Pyroptosis / immunology*
Receptor for Advanced Glycation End Products / immunology
Receptor for Advanced Glycation End Products / metabolism
Sepsis / genetics
Sepsis / immunology*
Sepsis / metabolism
THP-1 Cells

Substances

Endotoxins
HMGB1 Protein
Lipopolysaccharides
Receptor for Advanced Glycation End Products
Caspases
caspase 11, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding