Estrogen Prevents the Lipopolysaccharide-Induced Inflammatory Response in Microglia

Abstract

After neuronal injury and in several neurodegenerative diseases, activated microglia secrete proinflammatory molecules that can contribute to the progressive neural damage. The recent demonstration of a protective role of estrogen in neurodegenerative disorders in humans and experimental animal models led us to investigate whether this hormone regulates the inflammatory response in the CNS. We here show that estrogen exerts an anti-inflammatory activity on primary cultures of rat microglia, as suggested by the blockage of the phenotypic conversion associated with activation and by the prevention of lipopolysaccharide-induced production of inflammatory mediators: inducible form of NO synthase (iNOS), prostaglandin-E 2 (PGE 2 ), and metalloproteinase-9 (MMP-9). These effects are dose-dependent, maximal at 1 nM 17␤-estradiol, and can be blocked by the estrogen receptor (ER) antagonist ICI 182,780. The demonstration of ER␣ and ER␤ expression in microglia and macrophages and the observation of estrogen blockade of MMP-9 mRNA accumulation and MMP-9 promoter induction further support the hypothesis of a genomic activity of estrogen via intracellular receptors. This is the first report showing an anti-inflammatory activity of estrogen in microglia. Our study proposes a novel explanation for the protective effects of estrogen in neurodegenerative and inflammatory diseases and provides new molecular and cellular targets for the screening of ER ligands acting in the CNS.

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

“…The last decade witnessed increasing confidence on the anti-inflammatory effect of estrogens to the point that several Pharmaceutical Companies are presently developing estrogen receptor ligands as anti-inflammatory agents [87]. With regard to microglia, in the recent years our studies showed a major anti-inflammatory activity of estradiol in microglia activated by strong inflammatory stimuli such as lipopolysaccharide (LPS) [241]. This effect was antagonized by ICI182,780, an estrogen receptor antagonist, suggesting a receptor-mediated effect of the hormone and ERa appeared to be selectively involved in estradiol anti-inflammatory activity in brain macrophages ( [82,242]).…”

“…This evidence suggested a new treatment strategy for patients with PD and encouraging results are being obtained from pilot clinical studies assessing HT safety and effectiveness in PD [139]. Although a direct evidence for a role of estrogenmicroglia signalling in PD models is still lacking, clear evidence suggests that estrogen signalling in these cells prevent microglia activation induced by a number of endogenous or environmental factors ( [26,242,241]). It is presumed that the complementary action of estradiol on neurons, astrocyte and microglia may provide beneficial outcome and represents a potential pharmacological target for delaying or preventing PD symptoms.…”

“…Our laboratory provided evidence to demonstrate the ability of estradiol to control brain inflammatory cells reactivity ( [242,241]). We analysed the effects of the deprivation of endogenous estrogens or of HT on microglia reactivity in the APP23 mice [243].…”

“…The two ER proteins recognised so far, ERa and ERb, are intracellular proteins which activate genomic as well as nongenomic effectors in neural cells [145]. Through the use of the estrogen receptor antagonist ICI 182780 we and others initially ascribed hormone action in microglia to the activation of endogenous ERs, since this molecule was able to block the effect of estradiol ( [24,25,141,241]). Using ER-null mice several reports described the selective involvement of ERa in the anti-inflammatory and neuroprotective activity of estradiol against neuroinflammatory and vascular pathologies of the brain ( [62,80,185,242]).…”

Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation

“…It has tissue-specific effects on inflammatory cytokines (9)(10)(11)(12). For example, while estrogen enhances nitric oxide production in endothelial cells, it inhibits nitric oxide and prostaglandin E 2 (13) production in microglia. The effects of estrogen on inflammation in the joint could account for enhanced nociception that occurs with estrogen depletion.…”