Sex differences in brain inflammation in experimental stroke

描述（由申请人提供）：很少有中风实验室研究雌性动物或使用性别特异性的缺血性脑损伤细胞模型。在某种程度上，这是由于历史上的假设，即细胞/分子损伤和修复机制在男性和女性中是相同的。临床前动物实验数据的持续缺乏给临床试验人员在女性和男性身上测试新疗法带来了严重的证据缺口。在本研究中，我们验证了一个重要的假设，即脑和外周免疫系统之间缺血后炎症循环的进化受到生物性别的强烈影响，包括性别二态免疫细胞亚群和影响局灶性脑缺血后炎症细胞脑-脾-脑循环的关键炎症机制。目标1将测试

DESCRIPTION (provided by applicant): Few stroke laboratories study female animals or use cell models of ischemic brain injury that are sex-specific. In part, this is due to the historical assumption that cellular/molecular injury and repair mechanisms are the same in males vs. females. The persistent lack of pre-clinical animal data in both sexes poses a severe evidence gap for clinical trialists who will test new therapies in women and men. In this application, we test the overarching hypothesis that the evolution of post-ischemic inflammatory cycling between the brain and peripheral immune system is strongly influenced by biological sex, including sexually dimorphic immune cell subsets and key inflammatory mechanisms that affect brain-spleen-brain cycling of inflammatory cells after focal cerebral ischemia. Aim 1 will test the hypotheses that evolving cerebral ischemic injury elicits splenic damage in tandem with brain microvascular and parenchymal inflammation that is more profound and is mediated by different immunocyte populations (monocytes vs. T lymphocytes) in males vs. females. Aim 2 determines if T lymphocyte-mediated injury in post-ischemic brain is greater in females due to lower levels of peroxisome proliferator activated receptor alpha (PPAR¿) in T lymphocytes. These hypotheses predict that (a) while splenectomy benefits the injured brain of both sexes by eliminating immunocytes nurtured within the spleen, adoptive transfer of female vs. male T lymphocytes sensitized to focal cerebral ischemia into splenectomized same sex recipients selectively increases female cerebral damage more so than males following MCAO and that (b) female vulnerability to T lymphocyte-mediated injury is due in part to a lack of protective PPAR¿ signaling mechanisms. Aim 3 will evaluate whether monocyte trafficking from spleen to post- ischemic brain is sex-specific. The hypotheses are that (a) males exhibit an early and more robust recruitment of CD45highCD11b+ macrophages and CD11c+ dendritic cells into post-ischemic brain relative to females; (b) this recruitment is due in part to higher matrix metalloproteinase (MMP)-9 expression in male monocytes, thus facilitating their transmigration; (c) male mice deficient in CD11b+ (macrophage "knockout") or in CD11c+ myeloid cells (dendritic cell "knockout") will more greatly benefit by loss of these cells than will females following focal cerebral ischemia. Findings from this application could therefore lead to the development of new therapies for stroke such as PPAR¿ agonists for females and MMP-9 antagonists for males.