脑膜淋巴管：联通中枢神经系统与外周免疫的门户

樊镕; 罗宇翔; 高志华

doi:10.16098/j.issn.0529-1356.2024.04.003

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解剖学报 ›› 2024, Vol. 55 ›› Issue (4) : 393-398. DOI: 10.16098/j.issn.0529-1356.2024.04.003

脑科学进展综述

脑膜淋巴管：联通中枢神经系统与外周免疫的门户

樊镕¹罗宇翔²高志华^2*

作者信息 +

Meningeal lymphatics: a gateway connecting the central nervous system to peripheral immune system

FAN Rong¹LUO Yu-xiang²GAO Zhi-hua^2*

Author information +

文章历史 +

摘要

传统观点认为，大脑是一个免疫豁免的独立器官。但随着研究不断深入，脑膜淋巴管的发现颠覆了这一认知，它的存在表明大脑与外周免疫之间存在着直接的物理和功能联系。脑膜淋巴管不仅参与脑脊液引流，清除脑内代谢废物，也发挥免疫监视和维持脑内免疫稳态的作用，对中枢神经系统疾病的发生发展具有重要影响，是联通脑与外周免疫系统的重要门户。本综述围绕脑膜淋巴管的解剖学结构、生理功能及其在神经系统疾病中的作用进行回顾，总结近年来的研究进展，并展望与之相关的可能研究方向与临床应用前景。

Abstract

Traditionally, the brain was considered as an immune-privileged organ. However, the re-discoveries of meningeal lymphatic vessels have revolutionized our understanding, revealing direct physical and functional connections between the central nervous system and the peripheral immunity. Meningeal lymphatic vessels play a crucial role in draining cerebro-spinal fluid, clearing metabolic waste from the brain, eliciting immune surveillance and maintaining immune homeostasis within the brain. They are implicated in the pathogenesis and progression of multiple central nervous system diseases. This review mainly focuses on the anatomical structure and physiological functions of meningeal lymphatic vessels, with brief introduction to their role in neurological diseases. We summarize recent research advances in meningeal lymphatic vessels, and provide insights for further research and clinical applications.

导出引用

樊镕罗宇翔高志华. 脑膜淋巴管：联通中枢神经系统与外周免疫的门户[J]. 解剖学报. 2024, 55(4): 393-398 https://doi.org/10.16098/j.issn.0529-1356.2024.04.003

FAN Rong LUO Yu-xiang GAO Zhi-hua. Meningeal lymphatics: a gateway connecting the central nervous system to peripheral immune system[J]. Acta Anatomica Sinica. 2024, 55(4): 393-398 https://doi.org/10.16098/j.issn.0529-1356.2024.04.003

中图分类号： R322.81

参考文献

［1］Sandrone S, Moreno-Zambrano D, Kipnis J, et al. A (delayed) history of the brain lymphatic system ［J］. Nat Med, 2019, 25(4):538-540.
［2］Mezey é, Palkovits M. Neuroanatomy: forgotten findings of brain lymphatics ［J］. Nature, 2015, 524(7566):415.
［3］Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels ［J］. Nature, 2015, 523(7560):337-341.
［4］Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules ［J］. J Exp Med, 2015, 212(7):991-999.
［5］Absinta M, Ha SK, Nair G, et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI ［J］. Elife, 2017, 6:e29738.
［6］Castranova D, Samasa B, Venero Galanternik M, et al. Live imaging of intracranial lymphatics in the Zebrafish ［J］. Circ Res, 2021,128(1):42-58.
［7］Adil A, Ravi KN, Ashutosh K. Meningeal lymphatic vessels: their morphology, location, and clinical implications ［J］. Eur J Anat, 2021,25(2): 109-115.
［8］Ahn JH, Cho H, Kim JH, et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid ［J］. Nature, 2019,572(7767):62-66.
［9］Yoon JH, Jin H, Kim HJ, et al. Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage ［J］. Nature, 2024, 625(7996):768-777.
［10］Antila S, Karaman S, Nurmi H, et al. Development and plasticity of meningeal lymphatic vessels［J］. J Exp Med, 2017, 214(12):3645-3667.
［11］Künnapuu J, Bokharaie H, Jeltsch M. Proteolytic cleavages in the VEGF family: generating diversity among angiogenic VEGFs, essential for the activation of lymphangiogenic VEGFs ［J］. Biology (Basel), 2021,10(2):167.
［12］Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β ［J］. Sci Transl Med, 2012, 4(147):147ra111.
［13］Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders［J］. Lancet Neurol, 2018. 17(11): 1016-1024.
［14］Ma Q, Ineichen BV, Detmar M, et al. Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice ［J］. Nat Commun, 2017, 8(1):1434.
［15］Izen RM, Yamazaki T, Nishinaka-Arai Y, et al. Postnatal development of lymphatic vasculature in the brain meninges ［J］. Dev Dyn, 2018, 247(5):741-753.
［16］Van Hove H, Martens L, Scheyltjens I, et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment ［J］. Nat Neurosci, 2019, 22(6):1021-1035.
［17］Louveau A, Herz J, Alme MN, et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature ［J］. Nat Neurosci, 2018, 21(10):1380-1391.
［18］Louveau A, Da Mesquita S, Kipnis J. Lymphatics in neurological disorders: a neuro-lympho-vascular component of multiple sclerosis and Alzheimer’s disease ［J］? Neuron, 2016, 91(5):957-973.
［19］Rustenhoven J, Drieu A, Mamuladze T, et al. Functional characterization of the dural sinuses as a neuroimmune interface ［J］. Cell, 2021,184(4):1000-1016.e27.
［20］Scheltens P, Blennow K, Breteler MM, et al. Alzheimer’s disease ［J］. Lancet, 2016, 388(10043):5050517.
［21］Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease ［J］. Science, 2010, 330(6012):1774.
［22］Da Mesquita S, Louveau A, Vaccari A, et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease ［J］. Nature, 2018, 560(7717):185-191.
［23］Wang L, Zhang Y, Zhao Y, Marshall C, et al. Deep cervical lymph node ligation aggravates AD-like pathology of APP/PS1 mice ［J］. Brain Pathol, 2019,29(2):176-192.
［24］Wen YR, Yang JH, Wang X, et al. Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer’s disease ［J］. Neural Regen Res, 2018, 13(4):709-716.
［25］Pappolla M, Sambamurti K, Vidal R, et al. Evidence for lymphatic Aβ clearance in Alzheimer’s transgenic mice ［J］. Neurobiol Dis, 2014,71:215-219.
［26］Ding XB, Wang XX, Xia DH, et al. Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease ［J］. Nat Med, 2021,27(3):411-418.
［27］Boisserand LSB, Geraldo LH, Bouchart J, et al. VEGF-C prophylaxis favors lymphatic drainage and modulates neuroinflammation in a stroke model ［J］. J Exp Med, 2024, 221(4):e20221983.
［28］Yanev P, Poinsatte K, Hominick D, et al. Impaired meningeal lymphatic vessel development worsens stroke outcome ［J］. J Cereb Blood Flow Metab, 2020,40(2):263-275.
［29］Chen J, Wang L, Xu H, et al. Meningeal lymphatics clear erythrocytes that arise from subarachnoid hemorrhage ［J］. Nat Commun, 2020, 11(1):3159.
［30］Wang X, Zhang A, Yu Q, et al. Single-cell RNA sequencing and spatial transcriptomics reveal pathogenesis of meningeal lymphatic dysfunction after experimental subarachnoid hemorrhage ［J］. Adv Sci (Weinh), 2023, 10(21):e2301428.
［31］Wang YJ, Sun YR, Pei YH, et al. The lymphatic drainage systems in the brain: a novel target for ischemic stroke ［J］? Neural Regen Res, 2023, 18(3):485-491.
［32］Maas AIR, Menon DK, Manley GT, et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research ［J］. Lancet Neurol, 2022, 21(11):1004-1060.
［33］Hussain R, Tithof J, Wang W, et al. Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema ［J］. Nature, 2023, 623(7989):992-1000.
［34］Bolte AC, Dutta AB, Hurt ME, et al. Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis ［J］. Nat Commun, 2020, 11(1):4524.
［35］Lin JQ, Sun HX, Jiang HJ, et al. Meningeal lymphatics restoration and neurovascular protection synergistically improve traumatic brain injury treatment ［J］. Chem Eng J, 2023,471:144686.
［36］Hu X, Deng Q, Ma L, et al. Meningeal lymphatic vessels regulate brain tumor drainage and immunity ［J］. Cell Res, 2020, 30(3):229-243.
［37］Song E, Mao T, Dong H, et al. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours ［J］. Nature, 2020,577(7792):689-694.
［38］Li X, Qi L, Yang D, et al. Meningeal lymphatic vessels mediate neurotropic viral drainage from the central nervous system ［J］. Nat Neurosci, 2022, 25(5):577-587.