The Expression of Interleukin-1β is Regulated by DNA Methylation in Microglia to Mediate Postoperative Cognitive Dysfunction in Aged Mice

Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly individuals. Neuroinflammation is closely related to its occurrence. However, the exact molecular mechanism underlying this link is undetermined. This study aimed to establish a mouse model of POCD to explore the role of DNA methylation in regulating the expression of interleukin-1β (IL-1β), which mediates the occurrence of POCD in aged mice. The POCD model was established by exploratory laparotomy and evaluated by novel object and Y-maze tests. We also assessed IL-1β production in the dorsal hippocampus and the expression of the DNA methylation-related proteins DNA methyltransferase 3a (DNMT3a), DNA methyltransferase 3b (DNMT3b), and methyl CpG binding protein 2 (MeCP2). Methylation specific PCR (MSP), methylated DNA immunoprecipitation (MeDIP) and DNA methylation sequencing in IL-1β promoter were used to explore the regulation of IL-1β by DNA methylation in this model. Finally, Golgi-Cox staining and Western blotting were used to further explore the role and potential mechanisms of IL-1β in POCD. Cognitive impairment was observed in aged but not adult mice. In aged mice, the microglia cells in the dorsal hippocampus were activated, while the DNA methylation in the IL-1β promoter was decreased. Interestingly, the global DNA methylation in the dorsal hippocampus was unchanged. IL-1β inhibition prevented surgery-induced cognitive decline and dysfunction of synaptic plasticity. Overall, these results indicated that DNA methylation regulation of IL-1β expression may be an important mechanism increasing the susceptibility to POCD.