Gaudier-Diaz Monica M, Zhang Ning, Haines Adam H, Zhou Min, DeVries A Courtney
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Neuroscience Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Neuroscience Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Brain Res. 2017 Oct 15;1673:86-94. doi: 10.1016/j.brainres.2017.08.008. Epub 2017 Aug 12.
Social isolation is a risk factor for cardiovascular and cerebrovascular diseases, although the underlying mechanisms remain underspecified. Considering the potential of microglia to become sensitized by stressors and their role in neuroinflammation, we hypothesized that social isolation primes microglia, resulting in an exaggerated neuroimmune response to experimental cerebral ischemia. First, major histocompatibility complex II (MHC II) gene expression, an indicator of microglial priming, was compared between mice that were socially isolated or pair-housed. MHC II increased in the hippocampus and cortex of socially isolated mice, which is suggestive of isolation-induced microglial priming. In experiment 2, isolated and pair-housed mice underwent ∼8min of global cerebral ischemia. Hippocampal mRNA expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was significantly increased among both isolated and pair-housed ischemia groups relative to sham controls. Hippocampal expression of interleukin 1 beta (IL-1β) and cortical TNF-α, IL-1β and IL-6, were significantly increased 24-h post ischemia in isolated mice, but not pair-housed mice, relative to controls. Ischemia-induced increases in microglial cell body area and percent area fraction of ionized calcium binding adaptor molecule 1 (Iba-1) positive staining were also observed in isolated, but not pair-housed mice, relative to controls. For experiment 3, brain sections from socially isolated and pair-housed mice underwent 15min of oxygen glucose deprivation (OGD), an ex vivo model of cerebral ischemia. IL-6 gene expression was significantly elevated following OGD only in hippocampi from mice that had been socially isolated, indicating that isolation prior to ischemia is sufficient to modulate the neuroinflammatory response. Together, these data suggest microglial priming as a possible mechanism underlying the detrimental effects of social isolation on cerebral ischemia outcome.
社会隔离是心血管和脑血管疾病的一个风险因素，尽管其潜在机制仍未明确。考虑到小胶质细胞有被应激源致敏的可能性及其在神经炎症中的作用，我们推测社会隔离会使小胶质细胞致敏，从而导致对实验性脑缺血产生过度的神经免疫反应。首先，比较了处于社会隔离状态或成对饲养的小鼠之间主要组织相容性复合体II（MHC II）基因的表达情况，MHC II基因表达是小胶质细胞致敏的一个指标。社会隔离小鼠的海马体和皮质中MHC II增加，这表明隔离诱导了小胶质细胞致敏。在实验2中，将隔离饲养和成对饲养的小鼠进行约8分钟的全脑缺血。相对于假手术对照组，隔离饲养和成对饲养的缺血组小鼠海马体中肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）的mRNA表达均显著增加。相对于对照组，隔离饲养的小鼠在缺血后24小时海马体中白细胞介素1β（IL-1β）的表达以及皮质中TNF-α、IL-1β和IL-6的表达显著增加，而成对饲养的小鼠则没有。相对于对照组，在隔离饲养而非成对饲养的小鼠中也观察到缺血诱导的小胶质细胞胞体面积增加以及离子钙结合衔接分子1（Iba-1）阳性染色的面积百分比增加。在实验3中，将社会隔离和成对饲养的小鼠的脑切片进行15分钟的氧糖剥夺（OGD），这是一种脑缺血的体外模型。仅在社会隔离小鼠的海马体中，OGD后IL-6基因表达显著升高，这表明缺血前的隔离足以调节神经炎症反应。总之，这些数据表明小胶质细胞致敏可能是社会隔离对脑缺血结局产生有害影响的潜在机制。
