Sex Differences in Acute Neuroinflammation after Experimental Traumatic Brain Injury Are Mediated by Infiltrating Myeloid Cells
Sex Differences in Acute Neuroinflammation after Experimental Traumatic Brain Injury Are Mediated by Infiltrating Myeloid Cells
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DOI：
10.1089/neu.2018.6019
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发表时间：
2018-11-16
影响因子：
4.2
通讯作者：
Loane, David J.
中科院分区：
文献类型：
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作者：
Doran, Sarah J.;Ritzel, Rodney M.;Loane, David J.
与年龄匹配的雌性小鼠相比，成年雄性小鼠对中度至重度受控皮质撞击（CCI）的炎症反应显示出更大的胶质细胞活化。然而，常驻小胶质细胞和浸润的外周髓样细胞的相对贡献，这种性二态性神经炎症反应仍然不清楚。在此，12周龄的雄性和雌性C57 Bl/6小鼠进行假手术或CCI，并在损伤后1、3或7天收集脑样品，用于流式细胞术分析细胞因子、活性氧（ROS）和驻留小胶质细胞（CD 45（int）CD 11b+）与浸润性髓样细胞（CD 45（hi）CD 11b+）中的吞噬作用。还进行了运动（旋转棒，圆柱体测试），情感（开放领域）和认知（Y-迷宫）功能测试。我们证明，男性小胶质细胞有增加的吞噬活性和较高的活性氧水平在未受伤的大脑，而女性小胶质细胞有增加的生产肿瘤坏死因子（TNF）α和白细胞介素（IL）-1 β。CCI后，雄性动物在损伤后1天表现出外周髓样细胞的显著流入，随后在3天表现出常驻小胶质细胞的增殖。相反，雌性CCI小鼠的骨髓浸润和小胶质细胞活化反应显著降低。在任何时间，在驻留小胶质细胞或浸润细胞中均未观察到TNF α、IL-1 β、转化生长因子β、NOX 2、ROS产生或吞噬活性的性别差异。然而，在这些功能中，浸润性骨髓细胞比常驻小胶质细胞反应性更强。与雄性小鼠相比，雌性CCI小鼠在损伤后1天也具有改善的运动功能。因此，我们得出结论，性二型反应中度至重度CCI的结果从快速激活和浸润的促炎性骨髓细胞的大脑在男性，而不是女性，小鼠。
The inflammatory response to moderate-severe controlled cortical impact (CCI) in adult male mice has been shown to exhibit greater glial activation compared with age-matched female mice. However, the relative contributions of resident microglia and infiltrating peripheral myeloid cells to this sexually dimorphic neuroinflammatory responses remains unclear. Here, 12-week-old male and female C57Bl/6 mice were subjected to sham or CCI, and brain samples were collected at 1, 3, or 7 days post-injury for flow cytometry analysis of cytokines, reactive oxygen species (ROS), and phagocytosis in resident microglia (CD45(int)CD11b+) versus infiltrating myeloid cells (CD45(hi)CD11b+). Motor (rotarod, cylinder test), affect (open field), and cognitive (Y-maze) function tests also were performed. We demonstrate that male microglia had increased phagocytic activity and higher ROS levels in the non-injured brain, whereas female microglia had increased production of tumor necrosis factor (TNF) alpha and interleukin (IL)-1 beta. Following CCI, males showed a significant influx of peripheral myeloid cells by 1 day post-injury followed by proliferation of resident microglia at 3 days. In contrast, myeloid infiltration and microglial activation responses in female CCI mice were significantly reduced. No sex differences were observed for TNF alpha, IL-1 beta, transforming growth factor beta, NOX2, ROS production, or phagocytic activity in resident microglia or infiltrating cells at any time. However, across these functions, infiltrating myeloid cells were significantly more reactive than resident microglia. Female CCI mice also had improved motor function at 1 day post-injury compared with male mice. Thus, we conclude that sexually dimorphic responses to moderate-severe CCI result from the rapid activation and infiltration of pro-inflammatory myeloid cells to brain in male, but not female, mice.