Sepsis-associated encephalopathy (SAE) is a common complication that leads to long-term cognitive impairments and increased mortality in sepsis survivors. The mechanisms underlying this complication remain unclear and an effective intervention is lacking. Accumulating evidence suggests the nucleotide-binding domain-like receptor protein3 (NLRP3)/caspase-1 pathway is involved in several neurodegenerative diseases. Thus, we hypothesized that the NLRP3/caspase-1 pathway is involved in NLRP3-mediated pyroptosis, maturation and release of inflammatory cytokines, and cognitive deficits in SAE. We used the NLRP3 inhibitor MCC950 and the caspase-1 inhibitor Ac-YVAD-CMK to study the role of the NLRP3/caspase-1 pathway in pyroptosis and cognitive deficits in a mouse model of SAE. Mice were randomly assigned to one of six groups: sham+saline, sham+MCC950, sham+Ac-YVAD-CMK, cecal ligation and puncture (CLP)+saline, CLP+MCC950, and CLP+Ac-YVAD-CMK. Surviving mice underwent behavioral tests or had hippocampal tissues collected for histochemical analysis and biochemical assays. Our results show that CLP-induced hippocampus-dependent memory deficits are accompanied by increased NLRP3 and caspase-1 positive cells, and augmented protein levels of NLRP3, caspase-1, gasdermin-D, and pro-inflammatory cytokines in the hippocampus. In addition, administration of MCC950 or Ac-YVAD-CMK rescues cognitive deficits and ameliorates increased hippocampal NLRP3-mediated neuronal pyroptosis and pro-inflammatory cytokines. Our results suggest that the NLRP3/caspase-1 pathway-induced pyroptosis mediates cognitive deficits in a mouse model of SAE.

Background: Increasing evidence suggests that multiple or long-time exposure to general anaesthesia (GA) could be detrimental to cognitive development in young subjects and might also contribute to accelerated neurodegeneration in the elderly. Iron is essential for normal neuronal function, and excess iron in the brain is implicated in several neurodegenerative diseases. However, the role of iron in GA-induced neurotoxicity and cognitive deficits remains elusive. Methods: We used the primary hippocampal neurons and rodents including young rats and aged mice to examine whether GA impacted iron metabolism and whether the impact contributed to neuronal outcomes. In addition, a pharmacological suppression of iron metabolism was performed to explore the molecular mechanism underlying GA-mediated iron overload in the brain. Results: Our results demonstrated that GA, induced by intravenous ketamine or inhalational sevoflurane, disturbed iron homeostasis and caused iron overload in both in vitro hippocampal neuron culture and in vivo hippocampus. Interestingly, ketamine-or sevoflurane-induced cognitive deficits, very likely, resulted from a novel iron-dependent regulated cell death, ferroptosis. Notably, iron chelator deferiprone attenuated the GA-induced mitochondrial dysfunction, ferroptosis, and further cognitive deficits. Moreover, we found that GA-induced iron overload was activated by NMDAR-RASD1 signalling via DMT1 action in the brain. Conclusion: We conclude that disturbed iron metabolism may be involved in the pathogenesis of GA-induced neurotoxicity and cognitive deficits. Our study provides new vision for consideration in GA-associated neurological disorders.

Lipid overload results in lipid redistribution among metabolic organs such as liver, adipose, and muscle; therefore, the interplay between liver and other organs is important to maintain lipid homeostasis. Here, we show that liver responds to lipid overload first and sends hepatocyte-derived extracellular vesicles (EVs) targeting adipocytes to regulate adipogenesis and lipogenesis. Geranylgeranyl diphosphate synthase (Ggpps) expression in liver is enhanced by lipid overload and regulates EV secretion through Rab27A geranylgeranylation. Consistently, liver-specific Ggpps deficient mice have reduced fat adipose deposition. The levels of several EV-derived miRNAs in the plasma of non-alcoholic fatty liver disease (NAFLD) patients are positively correlated with body mass index (BMI), and these miRNAs enhance adipocyte lipid accumulation. Thus, we highlight an inter-organ mechanism whereby the liver senses different metabolic states and sends corresponding signals to remodel adipose tissue to adapt to metabolic changes in response to lipid overload.