Neuroinflammation creates an immune regulatory niche at the meningeal lymphatic vasculature near the cribriform plate

Abstract

Meningeal lymphatic vessels residing in the dural layer above the sinuses of the brain, meninges at the base of the brain, and near the cribriform plate have all been shown to drain fluid, cells, and antigens. We have previously reported that meningeal lymphatics near the cribriform plate undergo VEGFR3-dependent lymphangiogenesis during experimental autoimmune encephalomyelitis (EAE) to facilitate excess drainage. Using single-cell RNA sequencing (scRNA-seq), we report that neuroinflammation changes the phenotype and function of cribriform plate lymphatic endothelial cells (cpLECs). Upregulation of genes involved in antigen presentation, adhesion to leukocytes, and immunoregulatory molecules were verified by flow cytometry and functional assays.The inflamed cpLECs retain dendritic cells and to lesser extent CD4 T cells, creating an immune-regulatory niche that represents a previously underappreciated interface in the regulation of neuroinflammation. Additionally, the discontinuity of the arachnoid membrane near cpLECs provides unrestricted access to the cerebrospinal fluid (CSF) for immune surveillance. These findings may lead to new therapeutic approaches to neuroinflammatory diseases.

Immunological defense of CNS barriers against infections

“…This neural system is responsible for our sense of smell. Studies have shown that there are lymphatic vessels in the dura mater adjacent to the cribriform plate, and these vessels appear to access and sample CSF due to gaps in the arachnoid barrier ( Hsu et al., 2019 , 2022 ; Louveau et al., 2018 ). Studies also suggest that CSF can drain through the cribriform plate into the nasal lymphatics that reside outside of the skull ( Kida et al., 1993 ), although this finding is more controversial ( Louveau et al., 2018 ).…”

“…These data suggest that cribriform plate lymphatics drain primarily into the superficial cervical lymph nodes. During states of neuroinflammation, notable lymphangiogenesis was observed around the cribriform plate that did not occur with lymphatics along the dural venous sinuses ( Hsu et al., 2019 , 2021 , 2022 ; Louveau et al., 2018 ). The vulnerability of the olfactory system to nasal pathogens could explain why lymphatic vessels along the cribriform plate expand so readily in response to inflammatory stimuli.…”

“…The vulnerability of the olfactory system to nasal pathogens could explain why lymphatic vessels along the cribriform plate expand so readily in response to inflammatory stimuli. In addition, DCs were shown to be retained in this region during an inflammatory response, which could facilitate local antigen presentation to T cells ( Hsu et al., 2022 ). Antigen presentation along with lymphangiogenesis in cribriform-plate dura mater likely help protect the olfactory bulbs during the acute stages of an infection.…”

The emergence of the calvarial hematopoietic niche in health and disease

“…This included dendritic cells, myeloid cells, and CD4 + T cells. 49 Interestingly, these lymphatic vessels were further shown to capture and present CNS-derived antigens, with prime access to CSF provided by discontinuity of the arachnoid membrane near the cribriform plate. 49 Beyond EAE, meningeal lymphatic vessels have been reported to play varying roles with regards to improving or exacerbating disease pathology.…”

High-dimensional investigation of the cerebrospinal fluid to explore and monitor CNS immune responses

“…These concepts have been translated to murine disease models. Autoreactive T cells that recognize myelin oligodendrocyte glycoprotein (MOG) are negatively selected in the meninges [ 28 ] and neuroinflammation induces an immune regulatory niche in local meningeal lymphatic vasculature [ 31 ]. Disruption of meningeal lymphatics diminishes MS [ 32 ], but deteriorates Alzheimer’s disease (AD) [ 33 ] in mouse models.…”