A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland.
HiLIFE-Neuroscience Center, Helsinki University, Haartmaninkatu 8, 00290, Helsinki, Finland.
Sci Rep. 2022 May 25;12(1):8804. doi: 10.1038/s41598-022-12540-7.
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.
最近，人们在脑膜中发现了一套淋巴管系统，该系统被认为通过脑液引流在“清洁”大脑方面发挥作用。由于脑膜是偏头痛疼痛的起源部位，我们假设淋巴系统的功能障碍会影响局部三叉神经的痛觉。为了验证这一假设，我们研究了脑膜缺失的 K14-VEGFR3-Ig (K14) 小鼠的 hemiskull 制剂（包含脑膜）中的痛觉和炎症机制。我们记录脑膜传入神经的放电活动，并估计局部肥大细胞群、降钙素基因相关肽 (CGRP) 和细胞因子水平以及新鲜分离的 K14-VEGFR3-Ig (K14) 或野生型 C57BL/6 小鼠 (WT) 的硬脑膜三叉神经支配。在脑膜淋巴功能障碍的获得性模型 (AAV-mVEGFR3(1-4)Ig 诱导的淋巴消融) 中，我们证实了放电活动数据。我们发现，促炎细胞因子 IL12-p70 和 CGRP 的水平在 K14 小鼠的脑膜中降低，而肥大细胞激活剂 MCP-1 的水平增加。其他与偏头痛相关的促炎细胞因子（基础和刺激）在两种基因型之间没有差异。脑膜中三叉神经支配的模式保持不变，并且我们没有观察到与脑膜淋巴功能障碍相关的脑膜传入神经的基础或 ATP 诱导的痛觉放电发生改变。总之，脑膜淋巴管系统的缺失与促偏头痛和抗偏头痛介质之间的新平衡有关，但不会直接引发脑膜痛觉状态。
