Sex-, Stress-, and Sympathetic Post-Ganglionic Neuron-Dependent Changes in the Expression of Pro- and Anti-Inflammatory Mediators in Rat Dural Immune Cells.

ABSTRACT

BACKGROUND: Migraine 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. OBJECTIVE: Based 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. METHODS: Dura 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. RESULTS: In 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. CONCLUSIONS: Consistent 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.