Intracellular Lipopolysaccharide Sensing as a Potential Therapeutic Target for Sepsis
Abstract
Lipopolysaccharide (LPS) sensing in the cytosol by the noncanonical inflammasome leads to pyroptosis and NLRP3 inflammasome activation. This mechanism may be more critical for sepsis development than recognition of LPS by Toll-like receptor 4. LPS is directly binding to its intracellular receptor caspase-4/5/11, mediated by outer membrane vesicles and guanylate-binding proteins that deliver LPS to the cytosol and mediate access of caspases to LPS. Caspase-11-dependent cleavage of gasdermin D is discussed as a link between LPS-induced activation of caspases and pyroptosis or NLRP3 inflammasome activation. Finally, we highlight recently described inhibitors of cytosolic LPS-triggered noncanonical inflammasome activation that might be considered as potential drugs for the treatment of sepsis.
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High doses of endotoxin in blood cause a 'cytokine storm', septic shock and death, via activating TLR4, RAGE and caspases.
“High doses of endotoxin in blood (endotoxemia) cause a ‘cytokine storm’, septic shock and death, via activating TLR4, RAGE and caspases [16, 18, 20, 21].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [20]
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- Authors
- Pfalzgraff, A., & Weindl, G.
- Affiliations
- Freie Universität Berlin (DE)
- University of Bonn (DE)
- Corresponding author
- Weindl, Günther
- ORCID
- Weindl, Günther
- Venue
- Trends in Pharmacological Sciences
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 40
- Issue
- 3
- Pages
- 187-197
- ISSN
- 0165-6147 (ISSN-L)
- OpenAlex
- W2911973711
- Cited by
- 139
- References
- 93
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 29 · 2023: 20 · 2022: 15 · 2021: 24 · 2020: 17 · 2019: 10
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Pharmacological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- sepsis, lipopolysaccharide, non-canonical inflammasome, NLRP3 inflammasome, pyroptosis, caspase-11, gasdermin D, caspase-4, caspase-5, outer membrane vesicles, guanylate-binding proteins, TLR4, inflammasome inhibitors, therapeutic target
- MeSH terms
- Gasdermins, Animals, Humans, Lipopolysaccharides, Neoplasm Proteins, Sepsis, Caspases, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Inflammasomes, Molecular Targeted Therapy
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