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.


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


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