Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases

Abstract

The central nervous system (CNS) undergoes immunosurveillance despite the lack of conventional antigen presenting cells and lymphatic vessels in the CNS parenchyma. Additionally, the CNS is bathed in a cerebrospinal fluid (CSF). CSF is continuously produced, and consequently must continuously clear to maintain fluid homeostasis despite the lack of conventional lymphatics. During neuroinflammation, there is often an accumulation of fluid, antigens, and immune cells to affected areas of the brain parenchyma. Failure to effectively drain these factors may result in edema, prolonged immune response, and adverse clinical outcome as observed in conditions including traumatic brain injury, ischemic and hypoxic brain injury, CNS infection, multiple sclerosis (MS), and brain cancer. Consequently, there has been renewed interest surrounding the expansion of lymphatic vessels adjacent to the CNS which are now thought to be central in regulating the drainage of fluid, cells, and waste out of the CNS. These lymphatic vessels, found at the cribriform plate, dorsal dural meninges, base of the brain, and around the spinal cord have each been implicated to have important roles in various CNS diseases. In this review, we discuss the contribution of meningeal lymphatics to these processes during both steady-state conditions and neuroinflammation, as well as discuss some of the many still unknown aspects regarding the role of meningeal lymphatics in neuroinflammation. Specifically, we focus on the observed phenomenon of lymphangiogenesis by a subset of meningeal lymphatics near the cribriform plate during neuroinflammation, and discuss their potential roles in immunosurveillance, fluid clearance, and access to the CSF and CNS compartments. We propose that manipulating CNS lymphatics may be a new therapeutic way to treat CNS infections, stroke, and autoimmunity.

Aberrant waste disposal in neurodegeneration: why improved sleep could be the solution

“… [134] found that blocking the deep cervical lymph node drainage of APP/PS1 double-transgenic AD mice resulted in a significant deterioration of Aβ-related pathophysiology highlighting that this as an important exit route for brain clearance. While the olfactory route appears to be a major clearance route in animals, [19] , [53] , [107] recent evidence has questioned this in humans [90] , [111] . Both studies, which looked at the clearance of the MRI tracer gadobutrol, found little tracer in the nasal mucosa.…”

Immunological defense of CNS barriers against infections

“…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 Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans

“…With a rich microbiome populating the nasal cavity, resident bacteria can also gain access to the brain ( Zhou et al, 2014 ; Kumpitsch et al, 2019 ) as can proinflammatory cytokines ( Hsu et al, 2021b ). Imbalances in bacteria, referred to as dysbiosis and the associated host immune responses, have been implicated in upper respiratory chronic inflammatory diseases ( Wagner Mackenzie et al, 2017 ; Lee et al, 2018 ).…”