The innate immune system including microglia has a major contribution to maintenance
of the physiological functions of the hippocampus by permanent monitoring of the neural
milieu and elimination of tissue-damaging threats. The hippocampus is vulnerable to
age-related changes ranging from gene expression to network connectivity. The risk
of hippocampal deterioration increases with the decline of gonadal hormone supply.
To explore the impact of hormone milieu on the function of the innate immune system
in middle-aged female rats, we compared mRNA expression in the hippocampus after gonadal
hormone withdrawal, with or without subsequent estrogen replacement using estradiol
and isotype-selective estrogen receptor (ER) agonists. Targeted profiling assessed
the status of the innate immune system (macrophage-associated receptors, complement,
inhibitory neuronal ligands), local estradiol synthesis (P450 aromatase) and estrogen
reception (ER). Results established upregulation of macrophage-associated (Cd45, Iba1,
Cd68, Cd11b, Cd18, Fcgr1a, Fcgr2b) and complement (C3, factor B, properdin) genes
in response to ovariectomy. Ovariectomy upregulated Cd22 and downregulated semaphorin3A
(Sema3a) expression, indicating altered neuronal regulation of microglia. Ovariectomy
also led to downregulation of aromatase and upregulation of ERalpha gene. Of note,
analogous changes were observed in the hippocampus of postmenopausal women. In ovariectomized
rats, estradiol replacement attenuated Iba1, Cd11b, Fcgr1a, C3, increased mannose
receptor Mrc1, Cd163 and reversed Sema3a expression. In contrast, reduced expression
of aromatase was not reversed by estradiol. While the effects of ERalpha agonist closely
resembled those of estradiol, ERbeta agonist was also capable of attenuating the expression
of several macrophage-associated and complement genes. These data together indicate
that the innate immune system of the aging hippocampus is highly responsive to the
gonadal hormone milieu. In ovariectomized female rats, estradiol replacement exerts
potent immunomodulatory effects including attenuation of microglia sensitization,
initiation of M2-like activation and modulation of complement expression by targeting
hippocampal neurons and glial cells through ERalpha and ERbeta.
