Sex-, Stress-, and Sympathetic Post-Ganglionic Neuron-Dependent Changes in the Expression of Pro- and Anti-Inflammatory Mediators in Rat Dural Immune Cells.
Sex-, Stress-, and Sympathetic Post-Ganglionic Neuron-Dependent Changes in the Expression of Pro- and Anti-Inflammatory Mediators in Rat Dural Immune Cells.
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大鼠硬脑膜免疫细胞中促炎和抗炎介质表达的性别、应激和交感神经节后神经元依赖性变化。
作者：
McIlvried,LisaA;Borghesi,LisaA;Gold,MichaelS
背景偏头痛发作与硬脑膜无菌炎症有关。免疫细胞是炎症介质的主要来源，因此我们试图进一步探索硬脑膜免疫细胞与偏头痛之间的联系。目的根据偏头痛在女性中比男性更常见的观察，应激是偏头痛发作的最常见触发因素，并且交感节后硬脑膜神经支配使硬脑膜免疫细胞能够局部控制硬脑膜免疫细胞，我们假设应激使硬脑膜免疫细胞中炎症介质表达的平衡向引发偏头痛的细胞转移，这些变化在女性中更大，并且至少部分依赖于硬脑膜的交感节后神经支配。我们的目的是验证这一假说。方法硬脑膜取自幼稚或应激、完整或手术切除交感神经的成年雄性和雌性大鼠。在连续4天不可预测的、温和的应激源终止后，立即或24 小时对DURA进行评估。结果在髓系硬脑膜免疫细胞中，应激后，促炎症介质mRNA的表达增加，尤其是雌性，其表达水平在应激后持续升高，并在应激后24小时持续升高。女性在应激后立即出现抗炎介质mRNA的下降，但男性没有。在切断交感神经的女性中，应激诱导的变化被减弱。在淋巴来源的硬脑膜免疫细胞中，应激后促炎症介质的mRNA持续增加，特别是在女性。应激诱导的抗炎介质mRNA在男性和女性中均有增加，在切断交感神经的女性中进一步减弱。结论与我们的假设一致，应激诱导硬脑膜免疫细胞中促炎和抗炎介质表达的平衡发生变化，这种变化在女性中更为明显，至少部分依赖于女性的交感神经节后神经支配。炎症介质表达平衡的这种变化不仅可能在引发偏头痛发作方面发挥重要作用，而且还表明，如果不是必要的话，采用不同的策略来最有效地治疗男性和女性的偏头痛是可能的。
BackgroundMigraine attacks are associated with sterile inflammation of the dura. Immune cells are a primary source of inflammatory mediators, and we therefore sought to further explore the link between dural immune cells and migraine.ObjectiveBased on the observations that migraine is more common in women than in men, stress is the most common trigger for a migraine attack, and sympathetic post‐ganglionic innervation of the dura enables local control of dural immune cells, we hypothesized that stress shifts the balance of inflammatory mediator expression in dural immune cells toward those that trigger a migraine attack, where these changes are larger in females and dependent, at least in part, on sympathetic post‐ganglionic innervation of the dura. Our objective was to test this hypothesis.MethodsDura were obtained from naïve or stressed, intact or surgically sympathectomized, adult male and female rats. Dura were assessed immediately or 24 hours after termination of 4 continuous days of unpredictable, mild stressors. Following enzymatic digestion of each dura, myeloid and lymphoid‐derived dural immune cells were isolated by fluorescence‐activated cell sorting for semi‐quantitative polymerase chain reaction analysis.ResultsIn myeloid‐derived dural immune cells, there was an increase in pro‐inflammatory mediator mRNA following stress, particularly in females, which remained elevated with a 24‐hour delay after stress. There was a stress‐induced decrease in anti‐inflammatory mediator mRNA immediately after stress in females, but not males. The stress‐induced changes were attenuated in sympathectomized females. In lymphoid‐derived dural immune cells, there was a persistent increase in pro‐inflammatory mediator mRNA following stress, particularly in females. A stress‐induced increase in anti‐inflammatory mediator mRNA was also observed in both males and females, and was further attenuated in sympathectomized females.ConclusionsConsistent with our hypothesis, there is a stress‐induced shift in the balance of pro‐ and anti‐inflammatory mediator expression in dural immune cells that is more pronounced in females, and is dependent, at least in part, on sympathetic post‐ganglionic innervation in females. This shift in the balance of inflammatory mediator expression may not only play an important role in triggering migraine attacks, but also suggests it may be possible, if not necessary, to employ different strategies to most effectively treat migraine in men and women.