Estrogen receptor-α mediates the brain antiinflammatory activity of estradiol

Abstract

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.

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…With regard to microglia, in the recent years our studies showed a major anti-inflammatory activity of estradiol in microglia activated by strong inflammatory stimuli such as lipopolysaccharide (LPS) [241]. This effect was antagonized by ICI182,780, an estrogen receptor antagonist, suggesting a receptor-mediated effect of the hormone and ERa appeared to be selectively involved in estradiol anti-inflammatory activity in brain macrophages ( [82,242]). Other authors further confirmed these observations using primary cultures of microglia as well as cell lines and assaying estrogen-dependent attenuation of microglia activation in terms of reduced phagocytic activity, production of reactive oxygen and nitrogen species and other factors of the inflammatory cascade ( [26,43,61,141,262]).…”

“…In fact, estradiol does not alter the inflammatory signaling cascade in microglia if it is administered after inflammatory stimuli ( [26,82,242]); in addition, a prolonged hormonal deprivation affects estrogen protective activity in ischemia and causes a null or even opposite response to exogenous hormone administration [224]. Collectively, the experimental Fig.…”

“…This evidence suggested a new treatment strategy for patients with PD and encouraging results are being obtained from pilot clinical studies assessing HT safety and effectiveness in PD [139]. Although a direct evidence for a role of estrogenmicroglia signalling in PD models is still lacking, clear evidence suggests that estrogen signalling in these cells prevent microglia activation induced by a number of endogenous or environmental factors ( [26,242,241]). It is presumed that the complementary action of estradiol on neurons, astrocyte and microglia may provide beneficial outcome and represents a potential pharmacological target for delaying or preventing PD symptoms.…”

“…Our laboratory provided evidence to demonstrate the ability of estradiol to control brain inflammatory cells reactivity ( [242,241]). We analysed the effects of the deprivation of endogenous estrogens or of HT on microglia reactivity in the APP23 mice [243].…”

“…Through the use of the estrogen receptor antagonist ICI 182780 we and others initially ascribed hormone action in microglia to the activation of endogenous ERs, since this molecule was able to block the effect of estradiol ( [24,25,141,241]). Using ER-null mice several reports described the selective involvement of ERa in the anti-inflammatory and neuroprotective activity of estradiol against neuroinflammatory and vascular pathologies of the brain ( [62,80,185,242]). Despite the fact that ERb has been shown to be expressed widely in the CNS in adult mice ( [161,167]), it appears that this receptor isoform is not involved in mediating the protective effect of estrogens in neuroinflammatory diseases.…”