Estradiol inhibits ongoing autoimmune neuroinflammation and NFκB-dependent CCL2 expression in reactive astrocytes

Astroglial reactivity associated with increased production of NF kappa B-dependent proinflammatory molecules is an important component of the pathophysiology of chronic neurological disorders such as multiple sclerosis (MS). The use of estrogens as potential anti-inflammatory and neuroprotective drugs is a matter of debate. Using mouse experimental allergic encephalomyelitis (EAE) as a model of chronic neuroinflammation, we report that implants reproducing pregnancy levels of 17 beta-estradiol (E2) alleviate ongoing disease and decrease astrocytic production of CCL2, a proinflammatory chemokine that drives the local recruitment of inflammatory myeloid cells. Immunohistochemistry and confocal imaging reveal that, in spinal cord white matter EAE lesions, reactive astrocytes express estrogen receptor (ER)alpha (and to a lesser extent ER beta) with a preferential nuclear localization, whereas other cells including infiltrated leukocytes express ERs only in their membranes or cytosol. In cultured rodent astrocytes, E2 or an ER alpha agonist, but not an ER beta agonist, inhibits TNF alpha-induced CCL2 expression at nanomolar concentrations, and the ER antagonist ICI 182,170 blocks this effect. We show that this anti-inflammatory action is not associated with inhibition of NF kappa B nuclear translocation but rather involves direct repression of NF kappa B-dependent transcription. Chromatin immunoprecipitation assays further indicate that estrogen suppresses TNF alpha-induced NF kappa B recruitment to the CCL2 enhancer. These data uncover reactive astrocytes as an important target for nuclear ER alpha inhibitory action on chemokine expression and suggest that targeting astrocytic nuclear NF kappa B activation with estrogen receptor alpha modulators may improve therapies of chronic neurodegenerative disorders involving astroglial neuroinflammation.