Finally, experiments using DC deficient in ER-β revealed that the expression of ER-β on DC was GSK-3 activity essential for protective effects of ER-β ligand treatment in EAE. Our results demonstrate for the first time an effect of ER-β ligand treatment in vivo on DC in the target organ of a prototypic cell-mediated autoimmune disease. Pregnancy confers protection in a variety of cell-mediated autoimmune diseases in humans and in their respective animal models, including psoriasis, myasthenia gravis, Grave’s disease, rheumatoid
arthritis, and multiple sclerosis (MS) 1–4. Late pregnancy in humans has been associated with a decrease in Th1 immune responses. In MS, the reduction in Th1 immunity during late pregnancy is paralleled by a reduction in relapses 5. Estrogen treatment in the MS mouse model, experimental autoimmune encephalomyelitis, has been shown to reduce clinical disease by inhibiting a variety of disease-promoting mechanisms, including reductions in proinflammatory cytokines, chemokines, and migration factors, as well as increases Maraviroc solubility dmso in CD4+CD25+Foxp3+ T regulatory cells 6–10. Estrogens signal
primarily through two nuclear receptor subtypes, estrogen receptor (ER)-α and -β, whereas more rapid membrane effects have also been described 11, 12. Although both ER are expressed in all immune cell types, most of the protective effects of estrogen treatment in EAE have been shown to be mediated through ER-α without evidence for involvement of ER-β signaling 13–15. Recently, our lab has shown that ER-β ligand treatment during EAE reduced clinical
next disease relatively late and preserved axon densities despite a lack of an effect on decreasing CNS inflammation and altering peripheral cytokine production. This suggested a neuroprotective effect that was independent of influences on the peripheral immune system 16. However, an effect of ER-β ligand treatment on the composition and the function of immune cells in the target organ during EAE remained unknown. There is a great deal of evidence that APC localized to the CNS at sites of immune cell infiltration play a pivotal role in the outcome of neuroinflammation. The induction of EAE requires priming of antigen-specific CD4+ T cells (TC) in secondary lymphoid tissues, and re-activation of these CD4+ TC at the target organ by professional APC. DC can drive Th-cell differentiation and are potent APC that can influence innate and adaptive immune responses. DC in the healthy CNS normally reside in the meninges and around CNS blood vessels. Recent studies have shown that during adaptive immunity, mature myeloid DC preferentially accumulate at the perivascular inflammatory foci of the spinal cords during peak EAE disease severity, inducing the production of effector TC in the CNS 17–19. In a model where DC were the only cells expressing MHCII molecules, DC alone were sufficient to initiate EAE 20.