Estrogen Prevents the Lipopolysaccharide-Induced Inflammatory Response in Microglia

• DOI: 10.1523/jneurosci.21-06-01809.2001
• Publication Date: 2018-04-05T22:56:03Z
• Authors: Elisabetta Vegeto; Cinzia Bonincontro; Giuseppe Pollio; Angelo Sala; Serena Viappiani; Francesca Nardi; Alessia Brusadelli; Barbara Viviani; Paolo Ciana; Adriana Maggi
• Keywords: Inflammation; Lipopolysaccharides; 0303 health sciences; Dose-Response Relationship, Drug; Estradiol; Macrophages; Estrogen Antagonists; Estrogen Receptor alpha; Nitric Oxide Synthase Type II; Estrogens; Nitric Oxide; Dinoprostone; Monocytes; 3. Good health; 03 medical and health sciences; Matrix Metalloproteinase 9; Animals; Estrogen Receptor beta; Humans; Microglia; Nitric Oxide Synthase; Fulvestrant; Cells, Cultured

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 17beta-estradiol, and can be blocked by the estrogen receptor (ER) antagonist ICI 182,780. The demonstration of ERalpha and ERbeta 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.