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Review
. 2022 Sep 4;23(17):10139.
doi: 10.3390/ijms231710139.

Ocular Lymphatic and Glymphatic Systems: Implications for Retinal Health and Disease

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Review

Ocular Lymphatic and Glymphatic Systems: Implications for Retinal Health and Disease

Nasir Uddin et al. Int J Mol Sci. .

Abstract

Clearance of ocular fluid and metabolic waste is a critical function of the eye in health and disease. The eye has distinct fluid outflow pathways in both the anterior and posterior segments. Although the anterior outflow pathway is well characterized, little is known about posterior outflow routes. Recent studies suggest that lymphatic and glymphatic systems play an important role in the clearance of fluid and waste products from the posterior segment of the eye. The lymphatic system is a vascular network that runs parallel to the blood circulatory system. It plays an essential role in maintenance of fluid homeostasis and immune surveillance in the body. Recent studies have reported lymphatics in the cornea (under pathological conditions), ciliary body, choroid, and optic nerve meninges. The evidence of lymphatics in optic nerve meninges is, however, limited. An alternative lymphatic system termed the glymphatic system was recently discovered in the rodent eye and brain. This system is a glial cell-based perivascular network responsible for the clearance of interstitial fluid and metabolic waste. In this review, we will discuss our current knowledge of ocular lymphatic and glymphatic systems and their role in retinal degenerative diseases.

Keywords: age-related macular degeneration; aqueous humour; glaucoma; glymphatic pathway; lymphatic system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Aqueous humour outflow pathway. After secretion into the posterior chamber, aqueous humour enters the anterior chamber (light grey arrows) and leaves the eye through the trabecular meshwork (green arrows) and uveoscleral route (orange arrows). Figure inspired from [16].
Figure 2
Figure 2
Retinal fluid regulation pathway. Under normal conditions, water accumulates in the retina due to (1) metabolic activity, (2) influx from blood, and (3) influx from the vitreous chamber. Müller glia and RPE cells are responsible for water clearance from the inner and outer retina, respectively. This transcellular water transport is facilitated by the AQP4 water channel and is coupled to transport of potassium ions (K+) through the K+ channel. Figure inspired from [25].
Figure 3
Figure 3
CNS glymphatic pathway. CSF enters the brain parenchyma along the periarterial space, clears the waste products from the brain, and leaves the brain along the perivenous space. CSF flow into and through the brain interstitium is facilitated by astrocytic AQP4 water channels.
Figure 4
Figure 4
Ocular glymphatic system. Schematic showing the current understanding of the ocular glymphatic system. Following production, a major portion of AH leaves the eye via the anterior outflow pathway (brown arrows). A small portion of AH enters the vitreous chamber (green arrows), from where AH enters the neural retina due to intraocular pressure. In the retina, AH mixes with interstitial fluid and transport along retinal ganglion cell axons across the lamina cribrosa barrier. From there, AH leaves the axons, travel towards the perivenous space, and finally drains into cervical lymph nodes (blue arrow) via meningeal lymphatic vessels. Likewise, the optic nerve has a distinct glymphatic system. In this pathway, CSF from the sub-arachnoid space (SAS) enters the optic nerve parenchyma (purple arrows) along the periarterial space. Following glymphatic activity, CSF then leaves the optic nerve via perivenous space before draining into cervical lymph nodes via meningeal lymphatics.

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