Review articleLymphatic drainage system of the brain: A novel target for intervention of neurological diseases
Introduction
Lymphatic drainage is essential for maintenance of overall tissue water and solute balance, homeostasis, metabolism, and immunity. The lymphatic system is made up of a network of blind-ended capillaries that drain into larger vessels responsible for removing lymph that contains waste materials, fluid, proteins, and cells from the interstitial fluid (ISF) surrounding tissues and most organs (Clapham et al., 2010, Dissing-Olesen et al., 2015). Eventually, the lymphatic system drains to the venous system for recirculation (Foldi, 1999). Despite the high metabolic rate of brain tissue, the brain parenchyma lacks conventional lymphatic vessels like other peripheral tissues and organs. However, the central nervous system (CNS) has its own unique lymphatic drainage structures (Laman and Weller, 2012, Laman and Weller, 2013). The existence of an irregular lymphatic drainage system in vertebrate brain has been proposed based on physiological and immunological evidence of communication between brain parenchyma, extracellular space (ECS), perivascular spaces (PVS), perineural space, subarachnoid space (SAS), meningeal lymphatics and cervical lymph nodes.
These lymphatic drainage pathways or routes in the brain have been examined by using the different types of tracer dyes Indian ink (Zhang et al., 1992) and Evans blue, radioactive protein tracers (Bradbury et al., 1981, Szentistvanyi et al., 1984), and various fluorescent tracers with different molecular structure (Carare et al., 2008). In 2008, the Weller-Carare group suggested that the basement membranes (BM) of cerebral arteries contained a perivascular pathway for the lymphatic drainage of the brain parenchyma based on data obtained from studies using florescent tracers and confocal microscopy. In 2012, Iliff et al. (Iliff et al., 2012) discovered a brain-wide network of paravascular pathways surrounding arterioles, capillaries, and venules lined with astrocytic vascular endfeet utilizing two-photon imaging. The “glia lymphatic”, or “glymphatic” drainage system has been proposed by Nedergaard (2013), Iliff and Nedergaard (2013) and Jessen et al. (2015) that integrates cerebrospinal fluid (CSF) circulation and ISF exchange with brain parenchyma via aquaporin-4 (AQP4) water channels expressed in astrocytes. Remarkably, in 2015, Louveau et al. (2015) and Aspelund et al. (2015) independently characterized the presence of meningeal lymphatic vessels lined with typical lymphatic endothelial cells in the mouse brain, which confirmed earlier observations by Foldi et al. (1966) and Andres et al. (1987). Furthermore, Bower et al. (2017) and van Lessen et al. (2017), very recently, discovered meningeal mural lymphatic endothelial cells in the zebrafish. This new type of brain lymphatic cells functions as a ‘scavenger' and participate in meningeal angiogenesis. These novel data demonstrated how the brain uses its own inbuilt lymphatic drainage system to process ISF/CSF exchange, clean wastes, and carry fluid, macromolecules, and immune cells from brain toward the deep cervical lymph nodes (Kida et al., 1995).
There are several excellent reviews regarding the structure and functional characteristics of the unique lymphatic drainage system in the vertebrate brain. Weller et al., 2009, Weller et al., 1996 systematically analyzed pathways of lymphatic drainage defined by anatomical features and tracer studies in rodent and other species and their correlation with human brain. Comprehensive reviews (Brinker et al., 2014, Matsumae et al., 2016) based on new findings utilizing cellular, molecular, and neuroimaging techniques have demonstrated the intimate exchange between CSF and ISF utilizing the brain lymphatic drainage pathways. Jessen et al. (2015) reviewed the structural elements, organization, regulation and functions of the brain glymphatic system. Bakker et al. (2016) discussed the partially conflicting data on CSF and ISF circulation regulated by the peri- and paravascular drainage pathways, especially in the flow direction and the motive forces for both proposed pathways. Furthermore, Engelhardt et al. (2016) described the definition of vascular, glial, and lymphatic immune gateways of the CNS based on the anatomical distribution and their functions. Louveau et al. (2016) brought new insights to features of brain immune-biology. The existence of a classical lymphatic system in the CNS leads to “a revised perspective on tolerance and the immune privilege of the brain in the etiology and pathology of different neurological disorders”.
Given the immunological and pathophysiological significance of cerebral lymphatic drainage pathways, it is thus valuable to consider development of new therapeutic strategies targeting key elements (regions, cells, and protein transporters) of these pathways (Cho et al., 2016, Gradalski et al., 2015, Martin et al., 2011). Proposed targets include: interfering with transcriptional factor function, enzymes, cytokines and neuroendocrine factors to restore or improve impaired lymphatic drainage in the brain. Such treatments show potential for the prevention or treatment of age-related cerebral amyloid angiopathy (CAA), neurodegenerative diseases, cerebrovascular diseases, and their complications. Furthermore, because of the importance of lymphatic transportation in immunity and immunotherapy (Thomas et al., 2016), improvement of the brain lymphatic system may act to enhance the therapeutic potential of immunotherapy for Alzheimer's disease (AD), neuroinflammation, and brain tumors. More importantly, targeting the unique functional roles of lymphatic drainage pathways in dynamic communication between brain parenchyma and flow of extracellular fluids may prove advantageous for brain tissue-targeted gene therapy and drug delivery. Thus, the present review will focus on the therapeutic potential of translational research targets within the brain lymphatic drainage system and their regulators.
Section snippets
Key components of the brain lymphatic drainage system
The brain extracellular fluids include blood, CSF and ISF (Caversaccio et al., 1996, Knopf et al., 1995). The major portion of CSF is generated by epithelial cells of the choroid plexus in the cerebral ventricles, and at least 10% of CSF comes from ISF. The ISF originates mainly from fluids and metabolites secreted from the tissue and capillaries and partly from recycled CSF (Kodama et al., 2015, Liu et al., 2012). The SAS is a CSF reservoir located between the arachnoid membrane and the pia
Physiological functions and regulatory factors of the brain lymphatic drainage system
The brain lymphatic drainage system may play the role of lymphatic equivalent in the brain allowing high sensitivity of neurons and high metabolic capability of glia in response to dynamic changes occurring in their extracellular environment (Iliff et al., 2012) through interaction with the cerebral vascular system, parenchyma, and immune cells. The main physical functions of the brain lymphatic drainage system may include but are not limited to: a) clearance and reabsorption of macromolecular
Lymphatic drainage pathway-mediated communications between CNS and immune system
Even though the brain has been traditionally considered an “immune-privileged” organ, there are several studies showing multidirectional communications between the brain and the immune system. The concept of “immune reflex arc” and “immune surveillance circuit” (Romo-Gonzalez et al., 2012), similar to “neural reflex arc”, has been used to describe immune system function in brain. The afferent immune pathway refers to the presentation of antigens originating in the CNS to the immune system. The
Pathological significance of dysfunction of cerebral lymphatic drainage pathways in neurologic diseases
Disruption of the integrity of the cerebral lymphatic drainage system, which may occur with age or under different diseases or states (Selkoe and Weinberger, 2016, Smith et al., 2016a), such as severe trauma or brain injury (TBI, stroke, and subarachnoid hemorrhage (SAH)), may contribute to dyshomeostasis of the CNS extracellular environment and the processing of antigens drained from the in the brain parenchyma to regional lymph nodes. Furthermore, failure of the brain lymphatic drainage
Therapeutic or drug delivery strategies targeting key components of CNS lymphatic drainage pathways in neurological diseases
Developing strategies to improve impaired lymphatic drainage system function is a challenge for the prevention of age related effects and treatment of neurological diseases. Improving drainage in the brain lymphatic system may have a potential clinical significance in neurodegenerative, neurovascular and neuroinflammatory diseases by boosting the efficacy of immunotherapy treatment for AD and brain tumors (Woodworth et al., 2014).
Concluding remarks
The brain lymphatic drainage system consists of the BM-perivascular pathway, glymphatic system, the olfactory/cervical lymphatic drainage route and the meninges of a lymphatic network. The driving forces moving fluids and solutes in these pathways rely on vessel pulsations, intracranial pressure, osmotic gradients and various transporters. Even though co-existence of both perivascular pathway and glymphatic circulation is still a subject of debate, the integrated function of brain lymphatic
Conflicts of interest
None.
Acknowledgments
This work was supported in part by funds from the National Natural Science Foundation of China (Grant No. 81271275, 81070947, 30570651, 30670724 and 81471212 to B.-L. S) and the Natural Science Foundation of Shandong, China (Grant No. ZR2012HZ006 and Y2007C014 to B.-L. S.). We thank Cong Li, Lu-rong Shao, Hui-fang Zhang for their assistance in text editing and reference verification.
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B.-L. Sun and L.-H. Wang are co-first authors.