Due to compelling evidence supporting a link between sex, stress and sympathetic post-ganglionic innervation, dural immune cells and migraine, we recently characterized the impact of these factors on the type and number of immune cells in the dura. To determine whether a shift in dural immune cell phenotype may also contribute to the initiation of a migraine, we assessed the impact of these factors on the expression of inflammatory molecules. Dura tissue was obtained from naïve or stressed, intact or surgically sympathectomized (SPGNx), adult male or female rats. Stress consisted of continuous unpredictable, mild stressors over four days. Dura were collected immediately or 24 hr after stress termination. Cells were isolated following enzymatic digestion, and myeloid and lymphoid derived immune cells sorted with FACS for qPCR. There was a stress-induced increase in Il-6 expression that persisted for 24hr post stress, and a delayed stress-induced increase in TNFα expression in myeloid cells (> 89% macrophages) from both sexes. There was also an interaction between sex-, stress-, and SPGN-dependent regulation in iNOS, with a stress-induced increase in SPGNx females and the opposite in SPGNx males. Furthermore, there was a stress-induced decrease in IL-10 in both sexes, while POMC was only detected in males. Finally, there were also stress-induced increases in pro-inflammatory molecule expression (COX2), most pronounced in females (IL-1B, IL-6, COX1), in lymphoid cells (12.6% T-, 55.9% B-, 28.0% NK-, 2.6% NKT-cells). The regulation of immune cells in the dura is far more complex than originally suggested, and is influenced by sex, stress and SPGN innervation, as well as a significant interaction between these three factors. Our results raise the possibility that a shift in the balance of immune cell phenotype(s) may play an important role in the triggering of migraine attacks. Study supported by NIH grants NS083347 (MSG) and AI079047 (LAB).
© 2015 Published by Elsevier Inc.