文章基本信息

标题：Estrogen receptor-α mediates the brain antiinflammatory activity of estradiol
本地全文：下载
作者：Elisabetta Vegeto ; Silvia Belcredito ; Sabrina Etteri 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：16
页码：9614-9619
DOI：10.1073/pnas.1531957100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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{beta}-estradiol (E2) 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{beta}. 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.