Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, OR 97239-3098, USA
J Immunol. 2010 Apr 15;184(8):4087-94. doi: 10.4049/jimmunol.0902339. Epub 2010 Mar 19.
Reduced risk and severity of stroke in adult females is thought to depend on normal endogenous levels of estrogen, a well-known neuroprotectant and immunomodulator. In male mice, experimental stroke induces immunosuppression of the peripheral immune system, characterized by a reduction in spleen size and cell numbers and decreased cytokine and chemokine expression. However, stroke-induced immunosuppression has not been evaluated in female mice. To test the hypothesis that estradiol (E2) deficiency exacerbates immunosuppression after focal stroke in females, we evaluated the effect of middle cerebral artery occlusion on infarct size and peripheral and CNS immune responses in ovariectomized mice with or without sustained, controlled levels of 17-beta-E2 administered by s.c. implant or the putative membrane estrogen receptor agonist, G1. Both E2- and G1-replacement decreased infarct volume and partially restored splenocyte numbers. Moreover, E2-replacement increased splenocyte proliferation in response to stimulation with anti-CD3/CD28 Abs and normalized aberrant mRNA expression for cytokines, chemokines, and chemokine receptors and percentage of CD4(+)CD25(+)FoxP3(+) T regulatory cells observed in E2-deficient animals. These beneficial changes in peripheral immunity after E2 replacement were accompanied by a profound reduction in expression of the chemokine, MIP-2, and a 40-fold increased expression of CCR7 in the lesioned brain hemisphere. These results demonstrate for the first time that E2 replacement in ovariectomized female mice improves stroke-induced peripheral immunosuppression.
女性中风风险和严重程度降低被认为依赖于正常内源性雌激素水平,雌激素是一种众所周知的神经保护剂和免疫调节剂。在雄性小鼠中,实验性中风会导致外周免疫系统的免疫抑制,表现为脾脏缩小和细胞数量减少以及细胞因子和趋化因子表达降低。然而,尚未在雌性小鼠中评估中风诱导的免疫抑制。为了验证雌激素(E2)缺乏会加剧雌性小鼠局灶性中风后免疫抑制的假设,我们评估了大脑中动脉闭塞对卵巢切除小鼠的梗死面积以及外周和中枢免疫反应的影响,这些小鼠通过皮下植入或潜在的膜雌激素受体激动剂 G1 持续、受控水平地给予 17-β-E2。E2 和 G1 替代都减少了梗死体积并部分恢复了脾细胞数量。此外,E2 替代增加了对抗 CD3/CD28 Abs 刺激的脾细胞增殖,并使 E2 缺乏动物中观察到的细胞因子、趋化因子和趋化因子受体以及 CD4(+)CD25(+)FoxP3(+)T 调节细胞的异常 mRNA 表达正常化。E2 替代后外周免疫的这些有益变化伴随着趋化因子 MIP-2 的表达显著降低和损伤大脑半球中 CCR7 的表达增加 40 倍。这些结果首次表明,在卵巢切除的雌性小鼠中补充 E2 可改善中风引起的外周免疫抑制。