Brain Lymphatics and Neuronal Homeostasis

Brain Lymphatics & Neuronal Homeostasis

A few years ago, we discussed here the discovery of the brain lymphatic system and how this contributed to a paradigm shift, which reversed to a great extent the essential (and perhaps now obsolete) view of the brain as an organ cut off from the peripheral immune system. At the present, and as recently discussed by Diana Kwon, studies focus on how the immune system protects and interacts with brain cells in health and disease.

The brain and spinal cord are enclosed by meningeal linings formed by a tight connective tissue containing nerves, blood vessels, and lymphatic canals. Brain lymphatic drainage reaches the systemic circulation through cerebral veins (perivascular system) and dural lymphatics (paravascular system) within the meningeal connective tissue. On the other hand, blood-derived components only interact with the brain tissue when a pathogen or a pathology is present.

Early studies already reported the presence of circulating immune cells in the healthy brain, mostly in the choroid plexus and vessels within leptomeninges, but not in contact with the brain parenchyma. However, more recent works showed infiltrating T-cells in the cerebrospinal fluid (CSF) in close contact with the pia mater. However, the anatomical sites whereby circulating T cells may interact with dural resident cells in normal conditions was previously unclear.

Two structures located at the brain borders were first proposed as main routes for cell trafficking: the choroid plexus and the leptomeningeal vasculature. The leptomeninges are composed by the pia and the arachnoid mater. Between them, a subarachnoid space filled with CSF and penetrating vessels from the dura mater allows cell trafficking during inflammatory conditions.

However, during steady state conditions, the subarachnoid vasculature lacks the expression of cell-adhesion molecules and displays tight junction proteins connecting adjacent cells of the vascular tissue that prevents cell transmigration. The choroid plexus lines the cerebral ventricles and is composed by vascular secretory epithelial cells that secretes CSF into the ventricles. However, similar to the leptomeninges, the choroid plexus prevents blood-borne components entering the CNS by the presence of tight junctions between its cells.

Dural sinuses are blood channels that drains venous blood from the cranial cavity to the peripheral circulation. Those sinuses lie between the cranial endosteum and the dura matter in which CSF flows into through arachnoid granulations.

These sinuses were recently included as a potential brain-immune interface after Jonathan Kipnis and his group reported that CNS-derived proteins draining into the dura are captured by resident MHCII⁺ antigen-present cells (APCs) and presented to dural-circulating T lymphocytes, indicating active immune surveillance. Different from lymph nodes, where selectins and integrins coordinates cell homing, dural sinuses express P-selectin and PSGL-1 for cell recruitment. In fact, experimental studies showed that lymphocyte deficiency in animals disrupts brain homeostasis.

Initial studies reported that deficiency of B and T cells in the SCID mice decreases adult neurogenesis and causes severe cognitive impairments, such as a poor spatial learning, low performance in memory tasks, and decreased social interaction. In fact, transfer of healthy CD4+, but not CD8+, T cells to those immune-deficient animals rescued their cognitive and social performance, indicating the involvement of CD4 T cells in cognition.

Recently, studies showed that mice presenting non-functional T cells display a poor performance in tasks involving spatial and working memory compared to wild-type controls. Other studies also pointed other types of cognitive disabilities in those deficient mice, such as compulsive grooming and aberrant maternal behavior.

However, it is not clear how T lymphocytes modulate brain activity and animal behaviour, but studies pointed the involvement of inflammatory mediators, such as cytokines, released by those cells. For example, mice with normal T lymphocytes treated with neutralizing antibodies to IL-17 display signs of memory impairment and abnormal behavior.

Mice with a genetic deficiency to produce IL-4 or IFN-γ, cytokines greatly produced by T lymphocytes, present a poor learning ability and an intraperitoneal injection of the missing cytokine restores animal cognition and normalize cognitive task scores.

Those results indicate that cytokines, but not meningeal lymphocytes, interact with the brain tissue to modulate brain circuits and behaviour during a steady state condition. However, how cytokines modulate neuronal physiology and synaptic activity remains largely unknown.

Yet, some recent evidence indicates a link between cerebrospinal fluid IL-6 and depressive symptoms in humans or a link to autism-like symptoms in an experimental model of autism and/or cytokines as possible diagnostic markers in autism.

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Cover Image: Drainage of CSF via the meningeal lymphatic system. (A) Part of the CSF drains from the subarachnoid space via the lymphatic meningeal system. In turn, ISF drains to the subarachnoid space via the glymphatic system. These  routes allow the elimination of waste elements and macromolecules generated in the brain tissue. Adapted by permission from ref. 22, Springer Nature: Nature, copyright 2018. (B) The meningeal lymphatic vessels descend to the neck, where the cervical lymph nodes are located. These nodes are involved in the elimination of waste products (the scheme does not depict the lymphatic vessels lining the dural sinuses). Adapted from ref. 23. Copyright 2011 Elsevier Masson SAS. All rights reserved. From: Corpora amylacea act as containers that remove waste products from the brain. December 2019. Proceedings of the National Academy of Sciences 116(51):201913741 DOI:10.1073/pnas.1913741116 License CC BY-NC-ND 4.0.

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