The recent discovery of lymphatic vessels (LVs) in the dura mater, the outermost layer of meninges around the central nervous system (CNS), has opened a possibility for the development of alternative therapeutics for CNS disorders. The vascular endothelial growth factor C (VEGF-C)/VEGF receptor 3 (VEGFR3) signaling pathway is essential for the development and maintenance of dural LVs. However, its significance in mediating dural lymphatic function in CNS autoimmunity is unclear. We show that inhibition of the VEGF-C/VEGFR3 signaling pathway using a monoclonal VEGFR3-blocking antibody, a soluble VEGF-C/D trap, or deletion of the Vegfr3 gene in adult lymphatic endothelium causes notable regression and functional impairment of dural LVs but has no effect on the development of CNS autoimmunity in mice. During autoimmune neuroinflammation, the dura mater was only minimally affected, and neuroinflammation-induced helper T (T H ) cell recruitment, activation, and polarization were significantly less pronounced in the dura mater than in the CNS. In support of this notion, during autoimmune neuroinflammation, blood vascular endothelial cells in the cranial and spinal dura expressed lower levels of cell adhesion molecules and chemokines, and antigen-presenting cells (i.e., macrophages and dendritic cells) had lower expression of chemokines, MHC class II–associated molecules, and costimulatory molecules than their counterparts in the brain and spinal cord, respectively. The significantly weaker T H cell responses in the dura mater may explain why dural LVs do not contribute directly to CNS autoimmunity.

中文翻译：

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阻断 VEGFR3 信号导致硬脑膜淋巴管功能受损而不影响自身免疫性神经炎症

最近在硬脑膜（中枢神经系统 (CNS) 周围的脑膜最外层）中发现了淋巴管 (LV)，这为开发 CNS 疾病的替代疗法提供了可能性。血管内皮生长因子 C (VEGF-C)/VEGF 受体 3 (VEGFR3) 信号通路对于硬脑膜 LV 的发育和维持至关重要。然而，其在中枢神经系统自身免疫中介导硬脑膜淋巴功能的意义尚不清楚。我们表明，使用单克隆 VEGFR3 阻断抗体、可溶性 VEGF-C/D 陷阱或删除血管内皮生长因子3成人淋巴管内皮中的基因导致硬脑膜 LV 显着消退和功能损伤，但对小鼠中枢神经系统自身免疫的发展没有影响。在自身免疫性神经炎症期间，硬脑膜仅受到轻微影响，神经炎症诱导的辅助 T (TH) 硬脑膜中的细胞募集、激活和极化明显不如中枢神经系统明显。支持这一观点的是，在自身免疫性神经炎症期间，颅骨和脊髓硬脑膜中的血管内皮细胞表达较低水平的细胞粘附分子和趋化因子，抗原呈递细胞（即巨噬细胞和树突状细胞）的趋化因子、MHC 表达较低II 类相关分子和共刺激分子分别比大脑和脊髓中的对应分子高。明显较弱的 TH硬脑膜中的细胞反应可以解释为什么硬脑膜 LV 不直接促进 CNS 自身免疫。