The Endogenous Estrogen Status Regulates Microglia Reactivity in Animal Models of Neuroinflammation

Abstract

It has been previously demonstrated that 17beta-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 (Abeta) 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 Abeta deposits. Finally, we show that E(2) inhibits Abeta-induced expression of scavenger receptor-A in macrophage cells, providing a mechanism for the effect of E(2) on Abeta 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.

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

“…In parallel, we showed that estradiol is able to down-regulate inflammatory genes expression in brain: the increase in the mRNA for macrophage/monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and TNF-a induced by LPS injection in the cerebral ventricles was clearly restricted by hormone administration. Most interestingly, SR-A expression induced by Ab in macrophage cells was inhibited by estradiol pre-treatment, providing a potential mechanism for hormone inhibitory activity on microglia responsiveness observed in the APP23 mouse model [243].…”

“…We analysed the effects of the deprivation of endogenous estrogens or of HT on microglia reactivity in the APP23 mice [243]. We first observed that the number of plaques that were associated with reactive microglia increased with age, suggesting that the inflammatory reaction was indeed progressing in parallel with the disease.…”

Steroid hormone receptor expression and function in microglia

“…For instance, the SERM ICI-182,780, a pure antagonist of ERs, has strong effects preventing microglial activation, whereas estradiol has no effects under the same culture conditions (Suuronen et al, 2005;Tanaka et al, 1997). Yet, several reports support a pure anti-inflammatory role of estradiol (Baker et al, 2004;Bruce-Keller et al, 2000;Dimayuga et al, 2005;Ghisletti et al, 2005;Liu et al, 2005;Mor et al, 1999;Vegeto et al, 2003Vegeto et al, , 2006. Some recent papers have shown otherwise, namely, that ovary-derived estradiol is essential for mounting a proper inflammatory response to bacterial LPS, suggesting that circulating estradiol is exerting a permissive, pro-inflammatory effect (Soucy et al, 2005).…”

Estrogen and Brain Protection

“…The anti-inflammatory effects of estrogen were shown in a primary culture study; estrogen treatment decreased the expression of pro-inflammatory molecules, such as TNF-and IL-1 , as well as nitric oxide synthase and cyclooxygenase-2 in astrocytes (Valles et al, 2010). Vegeto et al (2006) conducted a study further supporting the protective effects of estrogen on inflammation associated with Alzheimer's disease. They used the APP23 mouse model, a model of Alzheimer's disease that creates chronic neuroinflammation resembling that in Alzheimer's disease.…”

“…They used the APP23 mouse model, a model of Alzheimer's disease that creates chronic neuroinflammation resembling that in Alzheimer's disease. They found that the number of plaques associated with reactive microglia was increased with age (Vegeto et al, 2006). Interestingly, ovariectomy accelerated microglial activation surrounding Amyloid plaques, whereas estrogen replacement delayed this process.…”