INTRODUCTION Stroke is a sexually dimorphic disease. While women account for more stroke deaths, recent data show that after adjusting for age and pre-stroke functional status, mortality is higher in men. Immune responses are key determinants of stroke outcome and may differ by sex. This study examined sex differences in central and peripheral T cell immune responses, systemic effects on gut permeability and microbiota diversity and behavioral outcomes after stroke in aged mice. We hypothesized that there are sex differences in the immune response to stroke in aged animals. METHODS C57BL/6N mice (20-22 months) were subjected to 60 min middle cerebral artery occlusion, or sham surgery. T cells were quantified in brain and blood at 3, 7 and 15 days (d) post-stroke by flow cytometry. Peripheral effects on gut permeability and microbiota diversity, as well as neurological function were assessed up to 14d, and at 21d (cognitive function) post-stroke. Brain glial fibrillary acidic protein (GFAP) expression was evaluated at 42d post-stroke. RESULTS AND DISCUSSION Mortality (50% vs 14%, p<0.05) and hemorrhagic transformation (44% vs 0%) were significantly higher in males than in females. No difference in infarct size at 3d were observed. Peripherally, stroke induced greater gut permeability of FITC-dextran in males at d3 (p<0.05), and non-reversible alterations in microbiota diversity in males. Following the sub-acute phase, both sexes demonstrated a time-dependent increase of CD4+ and CD8+ T cells in the brain, with significantly higher levels of CD8+ T cells and Regulatory T cells in males at d15 (p<0.01). Aged males demonstrated greater neurological deficits up to d5 and impaired sensorimotor function up to d15 when assessed by the corner asymmetry test (p<0.001 and p<0.01, respectively). A trend in greater cognitive decline was observed at d21 in males. Increased GFAP expression in the ischemic hemisphere, indicating astroglial activation and gliosis, was demonstrated in both males and females 42d post-stroke. Our findings indicate that despite a similar initial ischemic brain injury, aged male mice experience greater peripheral effects on the gut and ongoing central neuroinflammation past the sub-acute phase after stroke.

中文翻译：

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老年小鼠缺血性中风后 T 细胞免疫反应、肠道通透性和结果的性别差异

引言 中风是一种性二态性疾病。虽然女性中风死亡人数更多，但最近的数据显示，在调整年龄和中风前功能状态后，男性的死亡率更高。免疫反应是中风结果的关键决定因素，可能因性别而异。这项研究检查了老年小鼠中枢和外周 T 细胞免疫反应的性别差异、对肠道通透性和微生物群多样性的全身影响以及中风后的行为结果。我们假设老年动物对中风的免疫反应存在性别差异。方法 对 C57BL/6N 小鼠（20-22 个月）进行 60 分钟大脑中动脉闭塞或假手术。通过流式细胞术在中风后第 3、7 和 15 天 (d) 对大脑和血液中的 T 细胞进行定量。对肠道通透性和微生物群多样性的外周影响，以及中风​​后 14 天和 21 天（认知功能）评估神经功能。在中风后 42 天评估脑胶质纤维酸性蛋白 (GFAP) 表达。结果与讨论 男性的死亡率（50% 对 14%，p<0.05）和出血性转化（44% 对 0%）显着高于女性。未观察到第 3 天梗死面积的差异。在外周，中风在第 3 天诱导雄性 FITC-葡聚糖的肠道通透性更大（p<0.05），以及雄性微生物群多样性的不可逆改变。在亚急性期之后，两性都表现出大脑中 CD4+ 和 CD8+ T 细胞的时间依赖性增加，男性在第 15 天时 CD8+ T 细胞和调节性 T 细胞的水平显着升高（p<0.01）。当通过角不对称测试进行评估时，老年男性在 d5 之前表现出更大的神经功能缺损和感觉运动功能受损直至 d15（分别为 p<0.001 和 p<0.01）。在第 21 天，在男性中观察到认知能力下降更大的趋势。在中风后 42 天，男性和女性均证实了缺血半球 GFAP 表达增加，表明星形胶质细胞活化和神经胶质增生。我们的研究结果表明，尽管有类似的初始缺血性脑损伤，但老年雄性小鼠在中风后的亚急性期后会经历更大的肠道外周影响和持续的中枢神经炎症。在中风后 42 天，男性和女性均证实了缺血半球 GFAP 表达增加，表明星形胶质细胞活化和神经胶质增生。我们的研究结果表明，尽管有类似的初始缺血性脑损伤，但老年雄性小鼠在中风后的亚急性期后会经历更大的肠道外周影响和持续的中枢神经炎症。在中风后 42 天，男性和女性均证实了缺血半球 GFAP 表达增加，表明星形胶质细胞活化和神经胶质增生。我们的研究结果表明，尽管有类似的初始缺血性脑损伤，但老年雄性小鼠在中风后的亚急性期后会经历更大的肠道外周影响和持续的中枢神经炎症。