Abstract
The vertebrate CNS is surrounded by the meninges, a protective barrier comprised of the outer dura mater and the inner leptomeninges, which includes the arachnoid and pial layers. While the dura mater contains lymphatic vessels, no conventional lymphatics have been found within the brain or leptomeninges. However, non-lumenized cells called Brain/Mural Lymphatic Endothelial Cells or Fluorescent Granule Perithelial cells (muLECs/BLECs/FGPs) that share a developmental program and gene expression with peripheral lymphatic vessels have been described in the meninges of zebrafish. Here we identify a structurally and functionally similar cell type in the mammalian leptomeninges that we name Leptomeningeal Lymphatic Endothelial Cells (LLEC). As in zebrafish, LLECs express multiple lymphatic markers, containing very large, spherical inclusions, and develop independently from the meningeal macrophage lineage. Mouse LLECs also internalize macromolecules from the cerebrospinal fluid, including Amyloid-β, the toxic driver of Alzheimer’s disease progression. Finally, we identify morphologically similar cells co-expressing LLEC markers in human post-mortem leptomeninges. Given that LLECs share molecular, morphological, and functional characteristics with both lymphatics and macrophages, we propose they represent a novel, evolutionary conserved cell type with potential roles in homeostasis and immune organization of the meninges.
Highlights
The brain is surrounded by the meninges, a trilaminar compartment comprised of an outer dura mater, a middle arachnoid mater, and an inner layer of pia mater
Because MRC1 and LYVE1 are expressed in subsets of macrophages and dendritic cells, and VEGFR3 has been reported in peripheral, but not meningeal, macrophages [30, 71] we examined the leptomeninges for expression of the additional lymphatic endothelial marker, PROX1, which along with VEGFR3 has not been described in central nervous system (CNS) border macrophages [18, 29]
LYVE1 is expressed in meningeal macrophages, and immunogold electron microscopy (EM) labelled an ultrastructurally distinct population of rounded cells that possess numerous, irregularly shaped, heterogenous inclusions (Fig. 2f, g) that are characteristic of macrophages. Consistent with this interpretation, a similar macrophage-like cell type was observed in the meninges of Tg(flt4:mcitrine) zebrafish, but these cells were never labelled by immuno-EM against YFP, indicating that these cells lack canonical Brain Lymphatic Endothelial Cells (BLECs) marker expression. These results show that the ultrastructural distinctiveness of zebrafish BLECs is conserved in mouse Leptomeningeal Lymphatic Endothelial Cells (LLEC) and that these cells are a distinct population from CNS macrophages in both species
Summary
The brain is surrounded by the meninges, a trilaminar compartment comprised of an outer dura mater, a middle arachnoid mater, and an inner layer of pia mater. Under steady-state conditions, the meninges are replete with immune cells including macrophages, mast cells, B cells, and T cells that protect the brain from infection and. Understanding the mechanisms by which the meninges interact with the brain and surrounding CSF during both steady-state and diseased conditions have important clinical and therapeutic implications. Dorsal dural lymphatics can transport immune cells from the meninges and modulate T-cell activation during inflammation, and ablation studies of the dorsal dural lymphatics have demonstrated the importance of these vessels in the promotion of neuroinflammatory responses in an animal model of multiple sclerosis [37]. Dorsal dural lymphatic deletion studies suggest they participate in the drainage of waste from the CSF, including amyloid-β, which forms hallmark extracellular protein aggregates in Alzheimer’s disease [1, 44]. Enhancing dorsal dural lymphatic drainage of aged mice improved brain clearance and cognitive performance [44], highlighting the untapped therapeutic potential of targeting dural lymphatic function in age and disease
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