Background: With the advance of antibiotics and life support therapy, the mortality of sepsis has been decreasing in recent years. However, the incidence of sepsis-associated encephalopathy (SAE), a common complication of sepsis, is still high. There are few effective therapies to treat clinical SAE. We previously found that ethyl pyruvate (EP), a metabolite derivative, is able to effectively inhibit the NLRP3 inflammasome activation. Administration of ethyl pyruvate protects mice against polymicrobial sepsis in cecal ligation and puncture (CLP) model. The aim of present study is to investigate if ethyl pyruvate is able to attenuate SAE. Methods: After CLP, C57BL/6 mice were intraperitoneally or intrathecally injected with saline or ethyl pyruvate using the sham-operated mice as control. New Object Recognition (NOR) and Morris Water Maze (MWM) were conducted to determine the cognitive function. Brain pathology was assessed via immunohistochemistry. To investigate the mechanisms by which ethyl pyruvate prevent SAE, the activation of NLRP3 in the hippocampus and the microglia were determined using western blotting, and cognitive function, microglia activation, and neurogenesis were assessed using WT, Nlrp3 −/− and Asc −/− mice in the sublethal CLP model. In addition, Nlrp3 −/− and Asc −/− mice treated with saline or ethyl pyruvate were subjected to CLP. Results: Ethyl pyruvate treatment significantly attenuated CLP-induced cognitive decline, microglia activation, and impaired neurogenesis. In addition, EP significantly decreased the NLRP3 level in the hippocampus of the CLP mice, and inhibited the cleavage of IL-1β induced by NLRP3 inflammsome in microglia. NLRP3 and ASC deficiency demonstrated similar protective effects against SAE. Nlrp3 −/− and Asc −/− mice significantly improved cognitive function and brain pathology when compared with WT mice in the CLP models. Moreover, ethyl pyruvate did not have additional effects against SAE in Nlrp3 −/− and Asc −/− mice. Conclusion: The results demonstrated that ethyl pyruvate confers protection against SAE through inhibiting the NLRP3 inflammasome.
BackgroundCaspase-11, a cytosolic receptor of bacterial endotoxin (lipopolysaccharide: LPS), mediates immune responses and lethality in endotoxemia and experimental sepsis. However, the upstream pathways that regulate caspase-11 activation in endotoxemia and sepsis are not fully understood. The aim of this study is to test whether TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling is critical for caspase-11-dependent immune responses and lethality in endotoxemia.MethodsMice of indicated genotypes were subjected to endotoxemia or cecum ligation and puncture (CLP) and monitored daily by signs of a moribund state for lethality. Serum interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor (TNF) were measured by ELISA. Data were analyzed by using student’s t-test or one-way ANOVA followed by post-hoc Bonferroni test. Survival data were analyzed by using the log-rank test.ResultsBlockade of type 1 interferon signaling or genetic deletion of TRIF or guanylate-binding proteins (GBPs) prevented caspase-11-dependent immune responses, organ injury and lethality in endotoxemia and experimental sepsis. In vitro, deletion of GBPs blocked cytosolic LPS-induced caspase-11 activation in mouse macrophages.ConclusionsThese findings demonstrate that TRIF signaling is required for caspase-11-dependent immune responses and lethality in endotoxemia and sepsis, and provide novel mechanistic insights into how LPS induces caspase-11 activation during bacterial infection.
Double-stranded RNA dependent kinase R (PKR) is originally identified as an intracellular sensor of viral infection, but its role in bacterial infection remains largely unknown. Here we report that PKR was an important regulator of antibacterial immunity in sepsis. Genetic deletion of PKR or pharmacological inhibition of its kinase activity markedly increased bacterial loads, organ injury, and mortality in polymicrobial infection induced by cecal ligation and puncture (CLP). In contrast, PKR deficiency or inhibition did not affect bacterial loads, organ injury, or mortality when mice were systemically challenged with <i>Escherichia coli</i>, an abundant microbe in the gastrointestinal tract. PKR deficiency or inhibition markedly decreased the release of interleukin (IL)-1β after CLP. Defect in IL-1 signaling phenocopied PKR deficiency or inhibition in CLP-induced bacterial sepsis. Taken together, these findings identified a critical role of the PKR signaling pathway in antibacterial immunity.
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