Modulatory effect of estrogen on microglial activation

Abstract

Upon activation, brain macrophages, the microglia, release pro-inflammatory cytokines and inflammatory mediators. These neuroactive substances play important roles in eliciting inflammatory reaction associated with neurodegenerative process as seen in Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke. Activation of microglia in vivo is accompanied by intracellular accumulation of iron. Recent studies have shown that alteration of cellular iron levels modulates microglial inflammatory responses, as well as a set of functional genes identified by microarray analysis. Understanding the role of iron in activated microglia should provide insight into mechanisms of microglial activation and potential toxicity of iron-loaded activated microglia in neurodegeneration. Estrogen has been reported to exert its potential neuroprotective effect in AD and PD. In this study using an in vitro model of iron loaded LPS-activated microglia its effects on the secretion of MMP-9, nitric oxide (NO) and the expression of the iNOS, TNF -α and ILl-ß RNA. The results demonstrated that np-estradiol (E2) diminish MMP-9 secretion in iron loaded activated microglial cells still much more the MMP-9 activity in LPS-activated microglia. Furthermore, NO production could be suppressed significantly by l7ß-estradiol at l0nM in non-activated, as well as in LPS-activated microglia in the presence and absence of iron. Not only decreased the NO production but also reduced the NO levels significantly less than baseline in several conditions. Further studies revealed that treatment with E2 decrease the expression of iNOS and TNF-α in a dose-dependent manner. This study demonstrated that a higher dose of E2 increases the expression of the IL-1ß RNA in both non-activated and activated cells. However, treatment with E2 has no effect on the expression of the IL-1ß RNA in iron-loaded activated microglia. In conclusions, effector functions of activated microglia were different from that of iron-loaded activated microglia, suggesting the activation of microglia were linked to cellular iron metabolism. Intracellular iron loading modifies the responses of activated microglia to E2, suggesting iron could interfere with E2 actions. Therefore, these findings raise the precaution whether estrogen therapy would be an effective strategy for reversing the pathology of neurological diseases (e.g. AD) that involved brain iron accumulation and microglial activation