Irf6 participates in sevoflurane-induced perioperative neurocognitive disorder via modulating M2, but not M1 polarization of microglia

Perioperative neurocognitive disorder (PND) frequently occurs in elderly patients following anesthesia, and is associated with pro-inflammatory activation of microglia in hippocampus. In this study, sevoflurane, a commonly used inhaled anesthetic in clinic, was used to induce PND-like symptoms in aged SD rats (18-20 months). Data from novel object recognition and Y-maze tests first confirmed that aged SD rats exposed to 2% sevoflurane for 5 h developed cognitive impairment. Microglia preferred to polarizing towards pro-inflammatory M1 subtype (iNOS+Iba-1 +) in rat hippocampus post sevoflurane exposure, but not anti-inflammatory M2 subtype (Arg-1 +Iba-1 +). Microarray data identified interferon regulatory factor 6 (Irf6) as one (Fold change = -2.52, p = 0.006) of the 15 downregulated genes in hippocampus of the rats exposed to sevoflurane. Co-immunofluorescence data further illustrated that sevoflurane decreased Irf6 expression in hippocampal microglia. In vitro, sevoflurane enhanced lipopolysaccharide-induced M1 polarization of BV-2 cells and inhibited interleukin-4 induced M2 polarization. Interestingly, manipulation of Irf6 expression hardly affected M1 polarization. However, Irf6 overexpression further augmented the inhibitory effects on M2 polarization, and its silencing showed opposite effects. In addition, such M2 polarization-promoting effects of Irf6 knockdown may be associated with induction of peroxisome proliferator activated receptor gamma expression. Collectively, these findings suggest that Irf6 downregulation in hippocampal microglia may be a compensatory mechanism against sevoflurane-induced PND in the elderly.