1. Plexin C1 influences immune response to intracellular LPS and survival in murine sepsis.
- Author
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Bernard A, Eggstein C, Tang L, Keller M, Körner A, Mirakaj V, and Rosenberger P
- Subjects
- Animals, Mice, Mice, Knockout, Caspases, Initiator metabolism, Nerve Tissue Proteins metabolism, Nerve Tissue Proteins genetics, Receptors, Cell Surface metabolism, Receptors, Cell Surface genetics, Mice, Inbred C57BL, Male, Disease Models, Animal, Sepsis immunology, Sepsis metabolism, Lipopolysaccharides
- Abstract
Background: Intracellular sensing of lipopolysaccharide (LPS) is essential for the immune response against gram-negative bacteria and results in activation of caspase-11 and pyroptotic cell death with fatal consequences in sepsis. We found the neuronal guidance receptor plexin C1 (PLXNC1) influences the intracellular response to LPS., Methods: We employed a murine model of sepsis via cecal ligation and binding (CLP), using PLXNC1-/- mice and littermate controls, and additionally transfected murine bone-marrow-derived macrophages (BMDMs) from both genotypes with LPS to achieve activation of the noncanonical inflammasome ex vivo. Additionally, we transfected the PLXNC1 ligand SL4c-d in vivo and ex vivo to examine its effect on intracellular LPS response., Results: We found the neuronal guidance receptor PLXNC1 dampens the intracellular response to LPS by interacting with adenylate cyclase 4 (ADCY4) and protein kinase A activity, which in turn diminishes caspase-11 expression. The absence of PLXNC1 results in excessive inflammation marked by increased cytokine release, increased secondary organ injury and reduced sepsis survival in a murine sepsis model induced by CLP. Notably, administration of SL4c-d-peptide ligand of PLXNC1-reduces the inflammatory response during CLP-induced sepsis and improves survival., Conclusions: These results elucidate a previously unknown mechanism for PLXNC1 suppressing excessive noncanonical inflammasome activity and offer a new potential target for treatment of sepsis with its detrimental effects., (© 2024. The Author(s).)
- Published
- 2024
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