Meningeal lymphatics near the cribriform plate undergo lymphangiogenesis and directly engage in leukocyte crosstalk during neuroinflammation

Abstract

Abstract Meningeal lymphatics in the dural layer surrounding the dorsal regions of the brain, basal regions, and near the cribriform plate have all been implicated in the management of neuroinflammation and edema by facilitating the drainage of fluid, macromolecules, antigens, and cells. We have previously published that during neuroinflammation only the lymphatics near the cribriform plate are able to undergo extensive morphological changes through lymphangiogenesis in response to neuroinflammation during Experimental Autoimmune Encephalomyelitis (EAE), a mouse model of Multiple Sclerosis. In this study, we hypothesize that these cribriform plate lymphatics likely have other phenotypic changes as a consequence of neuroinflammation-induced lymphangiogenesis, and that identifying these phenotypic alterations may shed light on potentially novel roles of meningeal lymphatics during neuroinflammation. Single cell RNA sequencing reveals the upregulation of genes involved in leukocyte crosstalk and regulation such as chemotaxis/adhesion and antigen processing/presentation, suggesting that cribriform plate lymphatics may play a direct role in regulating adaptive immunity in addition to its canonical roles in facilitating drainage. We also demonstrate that cribriform plate lymphatics are able to capture CNS-derived antigens and functionally engage in crosstalk with dendritic cells and CD4 T cells. These data characterize cribriform plate lymphatics and demonstrate that these vessels become dynamic in response to neuroinflammation to facilitate excess drainage as well as directly modulate immunity through leukocyte crosstalk.