Estrogens regulate neuroinflammatory genes via estrogen receptors α and β in the frontal cortex of middle-aged female rats

Miklós Sárvári,Imre Kalló,Zsolt Liposits,István Likó,János Széles,Kinga Tóth,Sándor Mahó,Béla Molnár,Erik Hrabovszky,Norbert Solymosi

doi:10.1186/1742-2094-8-82

Abstract

BackgroundEstrogens exert anti-inflammatory and neuroprotective effects in the brain mainly via estrogen receptors α (ERα) and β (ERβ). These receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors. This study was aimed at the elucidation of the effects of ERα and ERβ agonists on the expression of neuroinflammatory genes in the frontal cortex of aging female rats.MethodsTo identify estrogen-responsive immunity/inflammation genes, we treated middle-aged, ovariectomized rats with 17β-estradiol (E2), ERα agonist 16α-lactone-estradiol (16α-LE2) and ERβ agonist diarylpropionitrile (DPN), or vehicle by Alzet minipump delivery for 29 days. Then we compared the transcriptomes of the frontal cortex of estrogen-deprived versus ER agonist-treated animals using Affymetrix Rat230 2.0 expression arrays and TaqMan-based quantitative real-time PCR. Microarray and PCR data were evaluated by using Bioconductor packages and the RealTime StatMiner software, respectively.ResultsMicroarray analysis revealed the transcriptional regulation of 21 immunity/inflammation genes by 16α-LE2. The subsequent comparative real-time PCR study analyzed the isotype specific effects of ER agonists on neuroinflammatory genes of primarily glial origin. E2 regulated the expression of sixteen genes, including down-regulation of complement C3 and C4b, Ccl2, Tgfb1, macrophage expressed gene Mpeg1, RT1-Aw2, Cx3cr1, Fcgr2b, Cd11b, Tlr4 and Tlr9, and up-regulation of defensin Np4 and RatNP-3b, IgG-2a, Il6 and ER gene Esr1. Similar to E2, both 16α-LE2 and DPN evoked up-regulation of defensins, IgG-2a and Il6, and down-regulation of C3 and its receptor Cd11b, Ccl2, RT1-Aw2 and Fcgr2b.ConclusionsThese findings provide evidence that E2, 16α-LE2 and DPN modulate the expression of neuroinflammatory genes in the frontal cortex of middle-aged female rats via both ERα and ERβ. We propose that ERβ is a promising target to suppress regulatory functions of glial cells in the E2-deprived female brain and in various neuroinflammatory diseases.

Highlights

Estrogens exert anti-inflammatory and neuroprotective effects in the brain mainly via estrogen receptors a (ERa) and b (ERb)
We examined the transcription of these genes involved in the recognition of danger- and pathogen-associated signals, cellular defense, phagocytosis, neuron-microglia communication and immune regulation after chronic treatments with E2, ERa agonist 16a-LE2 [21] and ERb agonist DPN [22]. We demonstrated that these ER agonists regulate the transcription of a large number of neuroinflammatory genes in the frontal cortex of middle-aged female rats
Expression profiling revealed numerous ERa agonistregulated immunity genes in the middle-aged female neocortex Oligonucleotide microarrays were used to study the effects of the selective ERa agonist 16a-LE2 on the cortical gene expression profile of middle-aged, ovariectomized rats

Summary

Introduction

Estrogens exert anti-inflammatory and neuroprotective effects in the brain mainly via estrogen receptors a (ERa) and b (ERb). These receptors are members of the nuclear receptor superfamily of liganddependent transcription factors. The complex interactions between the immune and central nervous systems govern the innate immune responses in the brain [1] Microglial cells survey their environment through continuous remodeling of cellular processes [2]. E2 inhibits the expression of pro-inflammatory cytokines IL1b and TNFa in LPStreated primary astrocytes [14] These studies indicate that E2 may regulate both microglia and astrocyte functions related to inflammation

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