Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies
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 th...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Karger Publishers
2021-05-01
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| Series: | Journal of Innate Immunity |
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| Online Access: | https://www.karger.com/Article/FullText/515740 |
| _version_ | 1818923199412305920 |
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| author | Ramy S. Gabarin Manshu Li Paige A. Zimmel John C. Marshall Yimin Li Haibo Zhang |
| author_facet | Ramy S. Gabarin Manshu Li Paige A. Zimmel John C. Marshall Yimin Li Haibo Zhang |
| author_sort | Ramy S. Gabarin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T02:05:38Z |
| format | Article |
| id | doaj.art-6de6e275f6984e42be693166356f3db4 |
| institution | Directory Open Access Journal |
| issn | 1662-811X 1662-8128 |
| language | English |
| last_indexed | 2024-12-20T02:05:38Z |
| publishDate | 2021-05-01 |
| publisher | Karger Publishers |
| record_format | Article |
| series | Journal of Innate Immunity |
| spelling | doaj.art-6de6e275f6984e42be693166356f3db42022-12-21T19:57:13ZengKarger PublishersJournal of Innate Immunity1662-811X1662-81282021-05-0111010.1159/000515740515740Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic StrategiesRamy S. Gabarin0Manshu Li1Paige A. Zimmel2John C. Marshall3Yimin Li4Haibo Zhang5Keenan Research Center for Biomedical Science of Unity Health Toronto, Toronto, ON, CanadaKeenan Research Center for Biomedical Science of Unity Health Toronto, Toronto, ON, CanadaKeenan Research Center for Biomedical Science of Unity Health Toronto, Toronto, ON, CanadaKeenan Research Center for Biomedical Science of Unity Health Toronto, Toronto, ON, CanadaKeenan Research Center for Biomedical Science of Unity Health Toronto, Toronto, ON, CanadaKeenan Research Center for Biomedical Science of Unity Health Toronto, Toronto, ON, CanadaSepsis 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.https://www.karger.com/Article/FullText/515740sepsislipopolysaccharideintracellular signalingpyroptosistherapy |
| spellingShingle | Ramy S. Gabarin Manshu Li Paige A. Zimmel John C. Marshall Yimin Li Haibo Zhang Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies Journal of Innate Immunity sepsis lipopolysaccharide intracellular signaling pyroptosis therapy |
| title | Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies |
| title_full | Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies |
| title_fullStr | Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies |
| title_full_unstemmed | Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies |
| title_short | Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies |
| title_sort | intracellular and extracellular lipopolysaccharide signaling in sepsis avenues for novel therapeutic strategies |
| topic | sepsis lipopolysaccharide intracellular signaling pyroptosis therapy |
| url | https://www.karger.com/Article/FullText/515740 |
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