The role of the meningeal lymphatic system in local inflammation and trigeminal nociception implicated in migraine pain

Abstract

AbstractBackgroundA system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in ‘cleaning’ the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the meninges of K14-VEGFR3-Ig mice lacking the meningeal lymphatic system.MethodsWe recorded the spiking activity of meningeal afferents and estimated the local mast cells infiltration, calcitonin gene-related peptide (CGRP) and cytokine levels (basal and stimulated), as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT).ResultsWe found that the meningeal level of CGRP and of the pro-inflammatory cytokines IL12-p70 and TNFα (implicated in migraine) were reduced in the meninges of K14 mice. On the contrary, in the meninges of K14 mice, we found an increased level of the mast cell activator MCP-1 and, consistently, a larger number of dural mast cells. The other migraine-related pro-inflammatory cytokines did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents.ConclusionsIn summary, the lack of meningeal lymphatic system does not induce migraine-like nociceptive state per se, but leads to a new balance between pro- and antiinflammatory factors implicated in migraine mechanisms.