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

Abstract

A 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 hemiskull preparations (containing the meninges) of K14-VEGFR3-Ig (K14) mice lacking the meningeal lymphatic system. We recorded the spiking activity of meningeal afferents and estimated the local mast cells population, calcitonin gene-related peptide (CGRP) and cytokine levels as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Spiking activity data have been confirmed in an acquired model of meningeal lymphatic dysfunction (AAV-mVEGFR3(1–4)Ig induced lymphatic ablation). We found that levels of the pro-inflammatory cytokine IL12-p70 and CGRP, implicated in migraine, were reduced in the meninges of K14 mice, while the levels of the mast cell activator MCP-1 were increased. The other migraine-related pro-inflammatory cytokines (basal and stimulated), 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 associated with meningeal lymphatic dysfunction. In summary, the lack of meningeal lymphatic system is associated with a new balance between pro- and anti-migraine mediators but does not directly trigger meningeal nociceptive state.

FM1-43 Dye Memorizes Piezo1 Activation in the Trigeminal Nociceptive System Implicated in Migraine Pain

“…In this case, we used a more reliable model for testing migraine pathology, such as an ex vivo meningeal preparation [ 17 , 18 ]. This selection was based on the emerging view that meningeal tissues, composed by blood and lymphatic vessels, multiple nerve fibers, and local immune cells, are supposed to be the origin site for migraine pain [ 17 , 19 , 20 , 21 ].…”

Natural killer cells and innate lymphoid cells 1 tune anxiety-like behavior and memory in mice via interferon-γ and acetylcholine

“…The effects of IFN-γ on GABAergic neurotransmission and on plasticity were described in hippocampal and prefrontal cortical neurons 22 , 23 , 64 , but we cannot exclude that the effects on GABAergic neurotransmission are mediated by glial cells or perivascular macrophages 65 , 66 . It has been demonstrated that local cytokines in the meningeal niche, such as IL-1 and IL-12, could induce the production of IFN-γ by NK cells 67 , 68 , but further studies will be necessary to better understand the molecular mechanisms that modulate IFN-γ production in the meninges.…”

Current views on meningeal lymphatics and immunity in aging and Alzheimer’s disease

“…Mast cells present in the vicinity of meningeal dural blood vessels and have been closely implicated in the modulation of brain function and in migraine development. Notably, recent work shows that early life stress has a profound impact on meningeal inflammation and drives dural mast cell activation, which then promoted anhedonic-like behaviour in mice [ 65 – 67 ]. However, we have a very little understanding about the nature of the systematic interactions between different subpopulations of dural immune cells, including mast cells, and how altered communication between them can predispose to increased proinflammatory cytokine secretion (e.g., TNF and calcitonin gene-related peptide) and mast cell activation in migraine.…”