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

It has been previously demonstrated that 17 beta-estradiol (E-2) inhibits the response of microglia, the resident brain macrophages, to acute injuries in specific brain regions. We here show that the effect of E-2 in acute brain inflammation is widespread and that the hormone reduces the expression of inflammatory mediators, such as monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and TNF-alpha, induced by lipopolysaccharide, 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 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 E-2 reverts the effects of ovariectomy 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 E-2 inhibits A beta-induced expression of scavenger receptor-A in macrophage cells, providing a mechanism for the effect of E-2 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.