Microglial hyperactivation and NLRP3 methylation mediated by SETD3 after anesthesia/surgery: Unraveling new mechanisms of perioperative neurocognitive disorders.

Abstract

AIMS: Postoperative cognitive disorders (PND) is a common complication in elderly patients after anesthesia and surgery. SETD3 has been suggested to play vital roles in the pathogenesis of neurological diseases. Therefore, this study aims to investigate the role of SETD3 in PND. METHODS: A PND mouse model was constructed by laparotomy under anesthesia. Mouse microglial cell line BV-2 were primed by lipopolysaccharide (LPS) and isoflurane were established to a neuroinflammation model of PND in vitro. Lentiviral vectors used for SETD3 knockdown were injected into the hippocampal DG region. Behavioral tests were conducted 4, 5 and 7-12 days after surgery. The expression of SETD3 and neuroinflammation-related cytokine (TNF-α, IL-6, and IL-1β) were test in the hippocampus. RESULTS: The SETD3 in the hippocampus 1 day after surgery at the mRNA and protein levels was upregulated. Furthermore, SETD3 expression was higher in the DG region than that in the CA1 and CA2/3 regions. Reducing SETD3 in the hippocampus DG region notably enhanced cognitive function following surgery. This reduction also significantly inhibited microglial overactivation and inflammatory cytokines. In vitro, knocking down the level of SETD3 in the hippocampus DG region could reduce the overactivation of microglia, with a decrease in the expression of inflammatory factors, whereas elevating the level of SETD3 exacerbated their overactivation. We examined the NLRP3-Caspase-1-IL-1β signaling pathway, finding that elevated SETD3 in the hippocampal DG region activated this pathway. Moreover, reducing SETD3 levels in vitro significantly lowered the H3K4 methylation of NLRP3 at its transcription start site. CONCLUSION: The results revealed that elevated SETD3 in the hippocampus DG region significantly activated NLRP3-Caspase-1-IL-1β signaling pathway by promoting H3K4 methylation, which enhanced neuroinflammation in the hippocampus and further led to learning and memory impairment after surgery.