Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies
| Autor: | Haibo Zhang, Ramy S Gabarin, Paige A Zimmel, Yimin Li, Manshu Li, John C. Marshall |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
Receptor complex Inflammasomes CD14 Inflammation Review Article sepsis Mice Extracellular medicine Immunology and Allergy Animals Internal medicine therapy Chemistry pyroptosis lipopolysaccharide intracellular signaling Pyroptosis Endothelial Cells Inflammasome RC31-1245 Cell biology TLR4 Medicine lipids (amino acids peptides and proteins) medicine.symptom Intracellular medicine.drug |
| Zdroj: | Journal of Innate Immunity, Pp 1-10 (2021) Journal of Innate Immunity |
| Popis: | Sepsis is defined as organ dysfunction due to a dysregulated systemic host response to infection. During gram-negative bacterial infection and other acute illness such as absorption from the gut infection, lipopolysaccharide (LPS) is a major mediator in sepsis. LPS is able to trigger inflammation through both intracellular and extracellular pathways. Classical interactions between LPS and host cells first involve LPS binding to LPS binding protein (LBP), a carrier. The LPS-LBP complex then binds to a receptor complex including the CD14, MD2, and toll-like receptor 4 (TLR4) proteins, initiating a signal cascade which triggers the secretion of pro-inflammatory cytokines. However, it has been established that LPS is also internalized by macrophages and endothelial cells through TLR4-independent pathways. Once internalized, LPS is able to bind to the cytosolic receptors caspases-4/5 in humans and the homologous caspase-11 in mice. Bound caspases-4/5 oligomerize and trigger the assembly of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome followed by the activation of inflammatory caspase-1 resulting in subsequent release of interleukin-1β. Caspases-4/5 also activate the perforin gasdermin D and purinergic receptor P2X7, inducing cell lysis and pyroptosis. Pyroptosis is a notable source of inflammation and damage to the lung endothelial barrier during sepsis. Thus, inhibition of caspases-4/5/1 or downstream effectors to block intracellular LPS signaling may be a promising therapeutic approach in adjunction with neutralizing extracellular LPS for treatment of sepsis. |
| Databáze: | OpenAIRE |
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