Estrogen receptor-beta ligand treatment modulates dendritic cells in the target organ during autoimmune demyelinating disease

Estrogens act upon nuclear estrogen receptors (ER) to ameliorate cell-mediated autoimmune disease. As most immunomodulatory effects of estrogens in EAE have been attributed to the function of ER-alpha, we previously demonstrated that ER-beta ligand treatment reduced disease severity without affecting peripheral cytokine production or levels of CNS inflammation, suggesting a direct neuroprotective effect; however, the effect of ER-beta treatment on the function of immune cells within the target organ remained unknown. Here, we used adoptive transfer studies to show that ER-beta ligand treatment was protective in the effector, but not the induction phase of EAE, as shown by decreased clinical disease severity with the preservation of axons and myelin in spinal cords. The analysis of the immune cell infiltrates in the CNS revealed that while ER-beta ligand treatment did not reduce overall levels of CNS inflammation, there was a decrease in the DC percentage, and these CNS DC had decreased TNF-alpha production. Finally, experiments using DC deficient in ER-beta revealed that the expression of ER-beta on DC was essential for protective effects of ER-beta ligand treatment in EAE. Our results demonstrate for the first time an effect of ER-beta ligand treatment in vivo on DC in the target organ of a prototypic cell-mediated autoimmune disease.