Lymph Flow Induces the Postnatal Formation of Mature and Functional Meningeal Lymphatic Vessels.

László Bálint,Petra Aradi,Bálint András Deák,Zsombor Ocskay,Zoltán Jakus

doi:10.3389/fimmu.2019.03043

László Bálint, Petra Aradi + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2019.03043

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Abstract

Recently, the presence of lymphatics has been demonstrated and characterized in the dura mater, which is in contrast to the well-accepted view indicating the lack of a classical lymphatic drainage system of the central nervous system (CNS). Moreover, the role of meningeal lymphatics in the pathogenesis of Alzheimer's disease and multiple sclerosis was suggested. However, the possible regulators of the developmental program and function of meningeal lymphatics remain unclear. Here, we aimed at characterizing the lymph flow dependence of the developmental program and function of the meningeal lymphatics. First, we demonstrated that lymphatics present in the dura mater are involved in the uptake and transport of macromolecules from the CNS. Meningeal lymphatics develop during the postnatal period which process involves the maturation of the vessels. The formation of mature meningeal lymphatics coincides with the increase of the drainage of macromolecules from the CNS to the deep cervical lymph nodes. Importantly, the structural remodeling and maturation of meningeal lymphatics is impaired in Plcγ2−/− mice with reduced lymph flow. Furthermore, macromolecule uptake and transport by the meningeal lymphatics are also affected in Plcγ2−/− mice. Collectively, lymph flow-induced mechanical forces are required for the postnatal formation of mature and functional meningeal lymphatic vessels. Defining lymph flow-dependence of the development and function of meningeal lymphatics may lead to better understanding of the pathogenesis of neurological diseases including Alzheimer's disease and multiple sclerosis.

Highlights

Until recently, the classical, well-accepted view was that the central nervous system (CNS) lacks lymphatic structures [1]
Our results indicate that meningeal lymphatic structures are involved in the uptake and transport of macromolecules from the CNS (Figures 2, 9)
While one part of the prior reports indicate that meningeal lymphatics participate in the transport of large molecules from the CNS, other studies were not able to detect the transport of macromolecules by meningeal lymphatics and indicated that further studies are needed to define their role in macromolecule and leukocyte transport [6, 7, 10, 11, 20]

Summary

Introduction

The classical, well-accepted view was that the central nervous system (CNS) lacks lymphatic structures [1]. Sporadic studies suggested the presence of lymphatic vessels in the dura mater. The first known report about the presence of meningeal lymphatic structures was published in 1787 by Mascagni, which was followed by others during the previous decades [2,3,4,5]. These early studies were not able to change the classical view. In 2015 two parallel studies described the presence of lymphatic structures in the dura mater in mouse models [6, 7]. The meningeal lymphatics were shown in non-human primates and humans, in which

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