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The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis
- Source :
- Immunity. 49:740-753.e7
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
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.
- Subjects :
- Lipopolysaccharides
Male
0301 basic medicine
Lipopolysaccharide
THP-1 Cells
media_common.quotation_subject
Receptor for Advanced Glycation End Products
Immunology
chemical and pharmacologic phenomena
Caspase-11
HMGB1
Article
Sepsis
03 medical and health sciences
chemistry.chemical_compound
Pyroptosis
medicine
Animals
Humans
Immunology and Allergy
HMGB1 Protein
Internalization
Cells, Cultured
media_common
Mice, Knockout
biology
Macrophages
Endothelial Cells
Inflammasome
medicine.disease
Cell biology
Endotoxins
Mice, Inbred C57BL
HEK293 Cells
030104 developmental biology
Infectious Diseases
medicine.anatomical_structure
chemistry
Caspases
Hepatocyte
biology.protein
lipids (amino acids, peptides, and proteins)
medicine.drug
Subjects
Details
- ISSN :
- 10747613
- Volume :
- 49
- Database :
- OpenAIRE
- Journal :
- Immunity
- Accession number :
- edsair.doi.dedup.....a9d73c39b23477b645e0002a48d1a493