Xu et al. reported that estrogen deficiency increased the expression of purinergic ligand-gated ion channel 7 receptor (P2X7R), toll-like receptor (TLR) 2 and TLR4 in the hippocampus of ovariectomized mice, promoted the inflammatory cascade reaction and the formation of the NLRP3 inflammasome, stimulated nuclear factor-κB (NF-κB), increased the expression of pro-IL-1β and pro-IL-18, and finally induced depression and anxiety-like behavior in mice. Here, TLR4 is linked to major depressive disorder.