The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis
Open accessAbstract
Graphical Abstract Figure. No caption available. SUMMARY 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. HIGHLIGHTSHepatocyte‐released HMGB1 mediates caspase‐11‐dependent lethality in sepsisHMGB1‐LPS complexes are taken up by macrophages and endothelial cells via RAGEHMGB1 destabilizes phagolysosomes for the transfer of LPS to cytosolic caspase‐11Neutralizing extracellular HMGB1 inhibits caspase‐11 activation in sepsis &NA; Caspase‐11, a cytosolic LPS receptor, mediates endotoxic shock. Deng and colleagues demonstrate that hepatocyte‐released HMGB1 mediates caspase‐11‐dependent pyroptosis and lethality in sepsis by delivering extracellular LPS into the cytosol of macrophages and endothelial cells, where LPS activates caspase‐11.
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Citations
Cites
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Metadata
- Authors
- Deng, M., Tang, Y., Li, W., Wang, X., Zhang, R., Zhang, X., Zhao, X., Liu, J., Tang, C., Liu, Z., Huang, Y., Peng, H., Xiao, L., Tang, D., Scott, M. J., Wang, Q., Liu, J., Xiao, X., Watkins, S., Li, J., Yang, H., Wang, H., Chen, F., Tracey, K. J., Billiar, T. R., & Lu, B.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 49
- Issue
- 4
- Pages
- 740-753.e7
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2896781864
- Cited by
- 591
- References
- 12
- FWCI
- 15.85
- Type
- journal article
- Language
- en
- Open access
- bronze
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