Evidence map›Paper›PMID 30314759›Full record

ArticleImmunity2018

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 and 16 more

Registry-linked trialAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Immunity, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04861922 (Low Dose Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection：a Pilot Study), which is not on this map. Cited by 360 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
360citing papers in PubMed, 2 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT04861922 phase3unknown statusnot on this mapstarted 2021, after this paper: background citation

Low Dose Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection：a Pilot Study

TypeinterventionalSponsorThe Third Xiangya Hospital of Central South UniversityRan2021 to 2024Enrolled100ConditionsSepsis, Gram-Negative Bacterial Infections, HeparinArmsUnfractionated Heparin
3 · Its place in the literature

Who cites it

360 citing papers in PubMed, 2 syntheses or guidelines pooled it.

  1. Pooled it
  2. Review: the role of GSDMD in sepsis.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022
    Pooled it
  3. Article
  4. Article
  5. Article
  6. Article
  7. Regulated cell death-induced coagulation dysfunction in sepsis.Journal of thrombosis and thrombolysis · 2026
    Review
  8. The role of HMGB1 in vascular endothelial cells.Apoptosis : an international journal on programmed cell death · 2026
    Review
  9. Review
  10. Review
  11. Article
  12. Review
  13. Review
  14. Review
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300 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

26 authors.

Meihong DengDepartment of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Yiting TangDepartment of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province 410000, P.R. China.
Wenbo LiDepartment 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.
Xiangyu WangDepartment 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.
Rui ZhangDepartment 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.
Xianying ZhangDepartment 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.
Xin ZhaoDepartment 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.
Jian LiuDepartment 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.
Cheng TangCollege of Life Science, Hunan Normal University, Changsha 410081, P.R. China.
Zhonghua LiuCollege of Life Science, Hunan Normal University, Changsha 410081, P.R. China.
Yongzhuo HuangShanghai Institute of Materia Medica, Chinese Academy of Science, 501 Hai-ke Rd, Shanghai 201203, P.R. China.
Huige PengShanghai Institute of Materia Medica, Chinese Academy of Science, 501 Hai-ke Rd, Shanghai 201203, P.R. China.
Lehui XiaoCollege of Chemistry, Nankai University, Tianjin 300073, P.R. China.
Daolin TangDepartment of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Melanie J ScottDepartment of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Qingde WangDepartment of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Jing LiuDepartment 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.
Xianzhong XiaoKey Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan Province 410000, P.R. China.
Simon WatkinsCenter for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Jianhua LiLaboratory of Biomedical Science, The Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.
Huan YangLaboratory of Biomedical Science, The Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.
Haichao WangDepartment of Emergency Medicine, North Shore University Hospital, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.
Fangping ChenDepartment 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.
Kevin J TraceyLaboratory of Biomedical Science, The Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.
Timothy R BilliarDepartment of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: billiartr@upmc.edu.
Ben LuDepartment 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.

Funding

Molecular Basis of Bioelectronic MedicineR35GM118182 · NIGMS · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · PI TRACEY, KEVIN J · 2016 to 2025
$7.3M
Mechanisms of Immune Dysfunction after Trauma and Surgical SepsisR35GM127027 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI TIMOTHY R BILLIAR · 2018 to 2026
$5.7M
Regulation and Function of Endotoxin Signaling in Surgical SepsisR01GM050441 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BILLIAR, TIMOTHY R · 1994 to 2018
$4.6M
Inflammasome activation in trauma-hemorrhagic shockR01GM102146 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI SCOTT, MELANIE J. · 2013 to 2025
$4.3M
Regulation of HMGB1 Release in Endotoxemia.R01GM063075 · NIGMS · NORTH SHORE UNIVERSITY HOSPITAL · PI WANG, HAICHAO · 2002 to 2020
$4.2M
Role of the ADAR1-mediated RNA editing ∕ RNA sensing axis in sterile inflammationR01AI139544 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI WANG, QINGDE · 2019 to 2023
$1.9M
Immunometabolism in SepsisR01GM115366 · NIGMS · UT SOUTHWESTERN MEDICAL CENTER · PI BILLIAR, TIMOTHY R, TANG, DAOLIN · 2015 to 2018
$1.2M
Function of a novel molecule ADAR1 in endothelial cells for angiogenesisR21AG052912 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI WANG, QINGDE · 2016 to 2017
$424k
NIAID NIH HHS R01 AI139544NIA NIH HHS R21 AG052912NIGMS NIH HHS R01 GM050441NIGMS NIH HHS R01 GM063075NIGMS NIH HHS R01 GM102146NIGMS NIH HHS R01 GM115366NIGMS NIH HHS R35 GM127027
6 · The paper itself

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.

Indexed as

AnimalsCaspasesCells, CulturedEndothelial CellsEndotoxinsHEK293 CellsHMGB1 ProteinHumansLipopolysaccharidesMacrophagesMaleMice, Inbred C57BLMice, KnockoutPyroptosisReceptor for Advanced Glycation End ProductsSepsiscaspase 11, humanCaspasesEndotoxinsHMGB1 ProteinLipopolysaccharidesReceptor for Advanced Glycation End Productscaspase-11endotoxemiaHMGB1inflammasomepyroptosissepsis

Identifiers

PMID30314759
PMCPMC6300139

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.