Estradiol Is Required for a Proper Immune Response to Bacterial and Viral Pathogens in the Female Brain

Abstract

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 (E2) 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-α, and IL-12 in microglial cells. Expression of these transcripts was largely inhibited in the brain of ovariectomized mice at time 24 h postchallenge. E2 replacement therapy totally rescued the ability of the endotoxin to trigger microglial cells and these permissive effects of E2 are mediated via the estrogen receptor (ER)α. Indeed, ERα-deficient mice exhibited an inappropriate reaction to LPS when compared with ERβ-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 E2 with their nuclear ERα 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 E2, which allows pathogens to hide from immune surveillance and exacerbates neuronal damages during viral encephalitis.

Elevated cytokine expression in the orbitofrontal cortex of victims of suicide

“…In this regard, it should be highlighted that while there is abundant information about gender differences in suicide risk factors and suicidal behavior, to our knowledge, postmortem studies have not reported major neurochemical or gene expression differences between the brain of suicides women and men. The observed sex-differences in cytokine expression in the present study may be of relevance because sex-differences in the immune and cytokine response of the brain have been reported in experimental animal models (46)(47)(48). Therefore, cytokines may further our understanding of neurochemical sex-differences in the brain that may be related to sex-differences in behavior.…”

Intranasal Immune Challenge Induces Sex-Dependent Depressive-Like Behavior and Cytokine Expression in the Brain

“…In the brain, enhanced immune responses in female with respect to male were reported in mice after i.n. inoculation with vesicular stomatitis virus (Barna et al, 1996), herpes simple virus-2 or intracerebral administration of LPS (Soucy et al, 2005). This has been proposed to be related to a stronger cytokine expression and transfer from innate to adaptive immune responses in females (Soucy et al, 2005) in which TNF-a have been shown to play an important role (Rahman and McFadden, 2006).…”

“…inoculation with vesicular stomatitis virus (Barna et al, 1996), herpes simple virus-2 or intracerebral administration of LPS (Soucy et al, 2005). This has been proposed to be related to a stronger cytokine expression and transfer from innate to adaptive immune responses in females (Soucy et al, 2005) in which TNF-a have been shown to play an important role (Rahman and McFadden, 2006). Relevant to this point, it has been recently shown that mice deficient in TNF-a receptors show reduced immobility time in the FST supporting a role for TNF-a in behavioral responses of depression (Simen et al, 2006).…”

Effects of estrogen receptor agonists on regulation of the inflammatory response in astrocytes from young adult and middle-aged female rats

“…However, other studies show that ERα may be necessary to mount an effective immune response. For example, ERKO mice do not show the expected increase in the LPS receptor TLR-2, after intracerebral LPS injections (Soucy et al, 2005), suggesting that the general innate immune response may be compromised in the absence of ERα.…”