Details

Autor(en) / Beteiligte

• Vegeto, Elisabetta
• Belcredito, Silvia
• Etteri, Sabrina
• Ghisletti, Serena
• Brusadelli, Alessia
• Meda, Clara
• Krust, Andrée
• Dupont, Sonia
• Ciana, Paolo
• Chambon, Pierre
• Maggi, Adriana

Titel

Estrogen Receptor-α Mediates the Brain Antiinflammatory Activity of Estradiol

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2003-08, Vol.100 (16), p.9614-9619

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2003

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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 17β-estradiol (E2) on neurons. Here we demonstrate that brain macrophages are also involved in E2action 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 α but not of ER β. The specific role of ER α 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 α is associated with a spontaneous reactive phenotype of microglia in specific brain regions of adult ER α-null mice. Altogether, these results reveal a previously undescribed function for E2in brain and provide a mechanism for its beneficial activity on neuroinflammatory pathologies. They also underline the key role of ER α in brain macrophage reactivity and hint toward the usefulness of ER α-specific drugs in hormone replacement therapy of inflammatory diseases.