In addition, E2 can inhibit the activation of microglia and astrocytes and reduce the expression of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 through TLR4/NF-κB signaling pathway [22], and our previous studies indicated that the occurrence and exacerbation of depression are closely related to the NF-κB-related signaling pathway in microglia [27] (Fig. 2). This evidence concerns the gene TLR4 and major depressive disorder.