Estrogen receptor-β ligand treatment modulates dendritic cells in the target organ during autoimmune demyelinating disease
Estrogen receptor-β ligand treatment modulates dendritic cells in the target organ during autoimmune demyelinating disease
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DOI：
10.1002/eji.201040796
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发表时间：
2011-01-01
影响因子：
5.4
通讯作者：
Voskuhl, Rhonda
中科院分区：
文献类型：
--
作者：
Du, Sienmi;Sandoval, Francisco;Voskuhl, Rhonda
雌激素作用于核雌激素受体（ER）以改善细胞介导的自身免疫性疾病。由于雌激素在EAE中的大多数免疫调节作用归因于ER-α的功能，我们先前证明ER-β配体治疗降低了疾病的严重程度，而不影响外周细胞因子的产生或CNS炎症的水平，这表明了直接的神经保护作用;然而，ER-β治疗对靶器官内免疫细胞功能的影响仍然未知。在这里，我们使用过继转移研究来表明ER-β配体治疗在效应器中是保护性的，但在EAE的诱导阶段不是，如通过保留脊髓中的轴突和髓鞘而降低临床疾病严重程度所示。对CNS中免疫细胞浸润的分析显示，虽然ER-β配体治疗没有降低CNS炎症的总体水平，但DC百分比降低，并且这些CNS DC具有降低的TNF-α产生。最后，使用ER-β缺陷的DC的实验显示，ER-β在DC上的表达对于ER-β配体处理在EAE中的保护作用是必需的。我们的研究结果首次证明了ER-β配体治疗对原型细胞介导的自身免疫性疾病靶器官中DC的体内作用。
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.