Abstract
A genuine and functional lymphatic vascular system is found in the meninges that sheath the central nervous system (CNS). This unexpected (re)discovery led to a reevaluation of CNS fluid and solute drainage mechanisms, neuroimmune interactions and the involvement of meningeal lymphatics in the initiation and progression of neurological disorders. In this manuscript, we provide an overview of the development, morphology and unique functional features of meningeal lymphatics. An outline of the different factors that affect meningeal lymphatic function, such as growth factor signaling and aging, and their impact on the continuous drainage of brain-derived molecules and meningeal immune cells into the cervical lymph nodes is also provided. We also highlight the most recent discoveries about the roles of the CNS-draining lymphatic vasculature in different pathologies that have a strong neuroinflammatory component, including brain trauma, tumors, and aging-associated neurodegenerative diseases like Alzheimer’s and Parkinson’s. Lastly, we provide a critical appraisal of the conundrums, challenges and exciting questions involving the meningeal lymphatic system that ought to be investigated in years to come.
Highlights
The lymphatic system mediates the drainage of interstitial fluid (ISF) and regulates immune cell trafficking and surveillance in the vast majority of mammalian tissues including the intestine, lungs, heart, liver, diaphragm, skin, eye and even in the meninges that enclose the central nervous system (CNS) (Escobedo and Oliver, 2016; Petrova and Koh, 2018; Oliver et al, 2020; Petrova and Koh, 2020)
Commitment to the lymphatic endothelial cells (LECs) lineage is dictated by vascular endothelial growth factor C (VEGF-C) signaling through vascular endothelial growth factor receptor 3 (VEGFR3) (Oh et al, 1997; Mäkinen et al, 2001; Mandriota et al, 2001)
This signaling pathway induces the downstream activation of the transcription factor SOX18 and expression of the genes encoding for prospero-related homeobox 1 (PROX1), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), podoplanin (PDPN) and C–C motif chemokine ligand (CCL) 21
Summary
The lymphatic vasculature is an important component of the circulatory system that was initially described back in the 17th and 18th centuries, by the pioneering works of Gasparo Aselli, Olaus Rudbeck, Thomas Bartholin and Paolo Mascagni (Natale et al, 2017; Sandrone et al, 2019). Despite recent reports showing VEGFR3expressing LECs imbedded in the leptomeninges (ShibataGermanos et al, 2020), and lymphatic processes reaching the pia mater (Cai et al, 2019), the current understanding is that the FIGURE 1 | Scheme depicting the structure of meningeal lymphatic vessels, lymphatic drainage of CSF solutes/molecules, mechanisms regulating the trafficking of immune cells through meningeal lymphatics and the unidirectional lymphatic flow into the brain draining CLNs. CCL19/21, C–C motif chemokine ligand 19/21; CCR7, C–C motif chemokine receptor 7; COS, confluence of sinuses; CSF, cerebrospinal fluid; LECs, lymphatic endothelial cells; LYVE-1, lymphatic vessel endothelial hyaluronan receptor-1; MMA, middle meningeal artery; PSS, petrosquamosal sinus; RRV, rostral rhinal vein; S1P, sphingosine-1-phosphate; S1PRs, sphingosine1-phosphate receptors; SMCs, smooth muscle cells; SS, sigmoid sinus; SSS, superior sagittal sinus; TS, transverse sinus.
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