Although the neuroprotective effects of estrogens are well recognized, the exact mechanisms involved in the ability of these sex steroids to protect the cerebral tissue still remain unclear. We tested in our study the hypothesis that estradiol (E(2)) modulates the innate immune response and expression of genes encoding proteins that a provide survival signal to neurons during infection. Mice received a single systemic or cerebral injection of LPS to trigger a robust but transient inflammatory reaction in the brain. The endotoxin increased transcriptional activation of genes encoding TLR2, TNF-alpha, and IL-12 in microglial cells. Expression of these transcripts was largely inhibited in the brain of ovariectomized mice at time 24 h postchallenge. E(2) replacement therapy totally rescued the ability of the endotoxin to trigger microglial cells and these permissive effects of E(2) are mediated via the estrogen receptor (ER)alpha. Indeed, ERalpha-deficient mice exhibited an inappropriate reaction to LPS when compared with ERbeta-deficient and wild-type mice. This defective innate immune response was also associated with a widespread viral replication and neurodegeneration in ovariectomized mice inoculated intranasally with HSV-2. These data provide evidence that interaction of E(2) with their nuclear ERalpha plays a critical role in the control of cytokines involved in the transfer from the innate to adaptive immunity. This transfer is deviant in mice lacking E(2), which allows pathogens to hide from immune surveillance and exacerbates neuronal damages during viral encephalitis.