Neuroprotection Effects of Sex Steroids in EAE

低剂量的性类固醇，包括17-f5雌二醇（E2）和睾酮（T4），可保护患者免受临床和 组织学实验性自身免疫性脑脊髓炎（EAE），一种人类疾病的动物模型， 硬化症（MS）。我们假设两种性类固醇对EAE的CNS神经保护作用是通过以下途径介导的： 免疫细胞和非免疫细胞。E2可能通过影响EAE的发育和功能， 髓鞘抗原特异性的潜在致病性T细胞，以及调节性T细胞，包括新的 描述了CD 4 + CD 25 + Treg细胞，这可能会改变疾病的进程。另一方面，E2的主要作用 可能在巨噬细胞、树突细胞或中枢神经系统细胞上。我们发现E2处理抑制了致脑炎活性， 髓鞘特异性T细胞，CNS和脾中细胞因子（特别是TNF-α）和趋化因子/受体减少， 并抑制炎性细胞向CNS的募集。最近，我们证明缺乏Esrl的ERKO小鼠 （E2受体）而不是缺乏Esr 2（E2受体P）的BERKO小鼠对E2介导的抑制是难治的。 慢性EAE，因此暗示Esrl在E2介导的保护中。在目标1中，我们将确定免疫或非免疫 细胞介导E2在慢性（C57 BL/6）和复发（SJL）EAE模型中的神经保护作用。在目标2中， 将继续研究表明E2可能增强CD 4 + CD 25 + T细胞调节活性的有希望的初步数据 也可能通过ESRL发挥作用。T4也可以提供对EAE的保护，正如我们之前所展示的那样。 在我们的年轻雄性小鼠模型中，阉割会使EAE恶化，而外源性T4治疗可以减轻疾病。我们 假设T4提供保护，因为它通过P450芳香酶转化为E2，这种作用是 在中年男性中最为明显。或者，T4可以通过雄激素直接信号传导起作用。 受体（AR）。在目标3中，我们将检验外源性T4治疗提供保护的假设， EAE通过酶转化，这是年龄依赖性的。该项目的成果将有选择地 鉴定EAE中E2反应细胞类型并确定雌激素和睾酮是否对EAE具有保护作用 利用重叠的机制，从而提供了与T4的神经保护机制的直接比较， 脑缺血（项目2）。我们的研究可能有助于预测睾丸激素如何使中- 老年MS患者

Low doses of sex steroids, including 17-f5 estradiol (E2) and testosterone (T4), confer protection against clinical and histological experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease, multiple sclerosis (MS). We hypothesize that the CNSneuroprotective effects of both sex steroids on EAE are mediated through both immune and non-immune cells. E2 may contribute to EAE resistance by influencingthe development and function of potentially pathogenic T cells specific for myelin antigens, as well as regulatory T cells, including the newly described CD4+CD25+ Treg cells, which might modify the course of disease. Alternatively, the primary effects of E2 might be on macrophages, dendritic cells, or CNS cells. We found that E2 treatment inhibited encephalitogenic activity of myelin-specific T cells, reduced cytokines (particularly TNF-a) and chemokines/receptors in the CNS and spleen, and inhibited recruitment of inflammatory cells into the CNS. Recently, we demonstrated that ERKO mice lackingEsrl (a receptor for E2) but not BERKO mice lacking Esr2 (P receptor for E2) were refractory to E2-mediated inhibition of chronic EAE, thus implicatingEsrl in E2-mediated protection. In Aim 1, we will determine if immune or non-immune cells mediate the neuroprotective effects of E2 in chronic (C57BL/6) and relapsing (SJL) models of EAE. In Aim 2, we will pursue promising preliminary data indicating that E2 may potentiate the regulatory activity of CD4+CD25+ T cells that may also function through Esrl. T4 may also provide protection from EAE, as we have previously shown. Castration worsens EAE in our young male mouse model, while exogenous T4 treatment reduces disease. We hypothesize that T4 provides protection because it is converted to E2 via the P450 aromatase, and this effect is most pronounced in middle-aged males. Alternatively, T4 may act by direct signaling through the androgen receptor (AR). In Aim 3, we will test the hypothesis that exogenous T4 treatment provides protection against EAE through enzymatic conversion that is age dependent. Results obtained from this project will selectively identify E2-responsive cell types in EAE and determine if estrogen and testosterone protection against EAE utilize overlapping mechanisms, thus providing a direct comparison with neuroprotective mechanisms of T4 in cerebral ischemia (Project 2). Our studies may be useful in predicting how testosterones might benefit middle- aged patients with MS.