IL-33/ST2 axis promotes remodeling of the extracellular matrix and drives protective microglial responses in the mouse model of perioperative neurocognitive disorders

•Anesthesia and surgery induce cognitive impairments via unclear mechanisms.•Microglia activity mediated by IL-33/ST2 plays a crucial role in perioperative neurocognitive disorders (PND).•IL-33 attenuated neuroinflammation and shifted the polarization of microglia in the hippocampus after anesthesia and surgery.•IL-33 rescued the increase of aggrecan, loss of dendritic spines, and impairment of LTP, improving cognitive performance. Anesthesia and surgery induce cognitive impairment via uncertain mechanisms. Increasing evidence has suggested that microglial activity mediated by IL-33 /ST2 plays a critical role in immune regulation and inflammatory responses. Yet, the implications for microglia activity mediated by IL-33 in perioperative neurocognitive disorders (PND) are not well established. We showed that IL-33 and ST2 were downregulated in the hippocampus after anesthesia and surgery, and the expression of aggrecan, remodeling by microglia, was upregulated. Meanwhile, the expression of pro-inflammatory cytokines (IL-6 and IL-1β) and M1-like microglia marker (iNOS) increased, and the expression of M2-like microglia marker (CD206) decreased. Notably, the administration of IL-33 attenuated neuroinflammation and shifted the polarization of microglia in the hippocampus after anesthesia and surgery. Furthermore, IL-33 treatment rescued the increase of aggrecan, loss of dendritic spines, and impairment of LTP, improving cognitive performance. In conclusion, our study suggests that microglia activity mediated by IL-33/ST2 plays a vital role in cognitive impairments after anesthesia and surgery, which may serve as a therapeutic target for PND.