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This version published online on February 9, 2006
Endocrinology, doi:10.1210/en.2005-1330
A more recent version of this article appeared on May 1, 2006
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Submitted on October 19, 2005
Accepted on January 27, 2006

The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation

Vegeto Elisabetta*, Belcredito Silvia, Ghisletti Serena, Meda Clara, Etteri Sabrina, and Maggi Adriana

Center of Excellence on Neurodegenerative Diseases and Dept. of Pharmacological Sciences, University of Milan, Milan, Italy

It has been previously demonstrated that 17{beta}-estradiol (E2) inhibits the response of microglia, the resident brain macrophages, to acute injuries in specific brain regions. We here show that the effect of E2 in acute brain inflammation is widespread and that the hormone reduces the expression of inflammatory mediators, such as MCP-1, MIP-2 and TNF-{alpha}, induced by LPS, demonstrating that microglia are a direct target of estrogen action in brain. Using the APP23 mice, an animal model of Alzheimer's Disease reproducing chronic neuroinflammation, we demonstrate that ovary ablation (ovx) increases microglia activation at {beta}-amyloid (A{beta}) deposits and facilitates the progression of these cells toward a highly reactive state. Long-term administration of E2 reverts the effects of ovx and decreases microglia reactivity compared with control animals. In this animal model, these events do not correlate with a reduced number of A{beta} deposits. Finally, we show that E2 inhibits A{beta}-induced expression of scavenger receptor-A in macrophage cells, providing a mechanism for the effect of E2 on A{beta} signaling observed in the APP23 mice.

Altogether, our observations reveal a substantial involvement of endogenous estrogen in neuroinflammatory processes and provide novel mechanisms for hormone action in the brain.
Key words: estrogen • brain inflammation • microglia




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