Beyond the key role in reproductive and cognitive functions, estrogens have been shown to protect against neurodegeneration associated with acute and chronic injuries of the adult brain. Current hypotheses reconcile this activity with a direct effect of 17␤-estradiol (E 2 ) on neurons. Here we demonstrate that brain macrophages are also involved in E2 action on the brain. Systemic administration of hormone prevents, in a time-and dose-dependent manner, the activation of microglia and the recruitment of peripheral monocytes induced by intraventricular injection of lipopolysaccharide. This effect occurs by limiting the expression of neuroinflammatory mediators, such as the matrix metalloproteinase 9 and lysosomal enzymes and complement C3 receptor, as well as by preventing morphological changes occurring in microglia during the inflammatory response. By injecting lipopolysaccharide in estrogen receptor (ER)-null mouse brains, we demonstrate that hormone action is mediated by activation of ER␣ but not of ER␤. The specific role of ER␣ is further confirmed by comparing the effects of ERs on the matrix metalloproteinase 9 promoter activity in transient transfection assays. Finally, we report that genetic ablation of ER␣ is associated with a spontaneous reactive phenotype of microglia in specific brain regions of adult ER␣-null mice. Altogether, these results reveal a previously undescribed function for E2 in brain and provide a mechanism for its beneficial activity on neuroinflammatory pathologies. They also underline the key role of ER␣ in brain macrophage reactivity and hint toward the usefulness of ER␣-specific drugs in hormone replacement therapy of inflammatory diseases.

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Abstract-Blood vessel cells express the 2 known estrogen receptors, ␣ and ␤ (ER␣, ER␤), which are thought to mediate estrogen inhibition of vascular injury and atherosclerosis, but the relative role of ER␣ and ER␤ in these events is controversial. Key Words: estrogen Ⅲ hormones Ⅲ vascular injury Ⅲ receptors Ⅲ animal models T he cardiovascular effects of steroid hormones are an area of intense interest at present. Estrogen has known systemic effects on circulating factors and has more recently been established to have direct effects on the blood vessel wall. Estrogen causes both rapid vascular dilatation and longer-term effects on gene expression in vascular cells (reviewed in Mendelsohn and Karas 1 ). At physiologically relevant concentrations of estrogen, studies support that estrogen receptors (ERs) ␣ and ␤ mediate both the rapid and the long-term cardiovascular effects of estrogen. ER␣ and ER␤ are expressed in both vascular endothelial and smooth muscle cells, but their physiological roles in the vasculature are incompletely understood.Using wild-type and estrogen receptor knockout mice, we have previously studied the role of ER␣ and ER␤ in mediating the vascular protective effects of estrogen in a mouse carotid artery injury model. 2,3,5,6 Studies of mice harboring single gene deletions of either ER␣ or ER␤ showed that treatment of ovariectomized female mice with nanomolar concentrations of 17␤-estradiol (E 2 ) inhibits the response to vascular injury to equivalent levels in wild-type mice, ER␣KO Chapel Hill (ER␣KO CH ) and ER␤KO CH . 2,5 These findings suggested that ER␣ and ER␤ are able to complement one another such that each receptor alone is sufficient to mediate the vascular protective effects of estrogen, or that the vascular protective effects of estrogen are mediated by an ER␣/ER␤-independent pathway. To distinguish between these 2 hypotheses, studies of vascular injury in ER␣,␤KO CH (double) estrogen receptor knockout mice were performed. 6 However, the effect of estrogen on vascular injury in these mice was complex. Although E 2 no longer inhibited the increases in medial carotid area after injury in the ER␣,␤KO CH mice, E 2 still significantly inhibited vascular smooth muscle cell (VSMC) proliferation after injury. In addition, E 2 also caused a significant increase in uterine weight in the ER␣,␤KO CH mice. 6 These data showed that the role of estrogen receptors could diverge for specific components of the vascular injury response in the ER␣,␤KO CH mice. However, the results left unresolved what is responsible for estrogen inhibition of VSMC proliferation and the increase in uterine weight in the ER␣,␤KO CH mice. These could be due to an unidentified third estrogen receptor or to residual function of protein from an ER␣ splice variant known to be expressed in the parental ER␣KO CH mice. 7 To resolve the question as to how estrogen Original