Meningeal Lymphatics in Central Nervous System Diseases

Abstract

Since its recent discovery, the meningeal lymphatic system has reshaped our understanding of central nervous system (CNS) fluid exchange, waste clearance, immune cell trafficking, and immune privilege. Meningeal lymphatics have also been demonstrated to functionally modify the outcome of neurological disorders and their responses to treatment, including brain tumors, inflammatory diseases such as multiple sclerosis, CNS injuries, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review, we discuss recent evidence of the contribution of meningeal lymphatics to neurological diseases, as well as the available experimental methods for manipulating meningeal lymphatics in these conditions. Finally, we also provide a discussion of the pressing questions and challenges in utilizing meningeal lymphatics as a prime target for CNS therapeutic intervention and possibly drug delivery for brain disorders.

Keywords: central nervous system; drainage; lymphatic vessels; meninges; neurodegeneration; neuroimmunology.

Figure 1

Aspects of neurological diseases affected by meningeal lymphatic vessels. Summary of neurological diseases discussed in this review and the multiple facets regulated by meningeal lymphatic (dys)function. Figure adapted from images created with Biorender.com.

Figure 2

Cranial meningeal lymphatic functions and predicted interactions with brain border compartments. Meningeal lymphatic vessels modulate the drainage of macromolecules and cells into deep cervical lymph nodes. They can also regulate cerebrospinal fluid (CSF) perfusion and interstitial fluid (ISF) efflux in the brain parenchyma. (a) Meningeal lymphatics may alter components of the CSF that instruct the skull bone marrow. This feature may affect myeloid cell differentiation in response to central nervous system (CNS) injury or the maintenance of the hematopoietic stem cell niche. (b) Changes in meningeal lymphatics can profoundly alter the meningeal immune cell landscape, potentially modifying the cytokine milieu that can affect brain physiology or impair meningeal lymphatic vessels through interferon gamma (IFN-γ) signaling. Alterations in meningeal immunity may also influence the nonhematopoietic compartment of the meninges. (c) Manipulation of meningeal lymphatic vessels can impact the delivery and processing of brain-derived antigens in deep cervical lymph nodes (dCLNs), which can shape the development of the local adaptive immune response. (d) Meningeal lymphatics can influence CSF/ISF flow in the brain parenchyma and microglial activation. These reported changes can influence the integrity of the blood-brain barrier and neuronal physiology, which can then promote changes in cognitive performance. Solid arrows represent information that has been reported in publications, whereas dashed arrows show that further investigation is required. Figure adapted from images created with Biorender.com. Center meninges/brain image adapted with permission from Louveau et al. (2016).