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Advances in the Understanding of ocular and nasal lymphatics

BMC Immunology volume 26, Article number: 16 (2025) Cite this article

Abstract

Recent research advancements have enhanced our understanding of the lymphatic system in the eye and nasal region and its involvement in health and disease. The eye is an anatomical extension of the central nervous system and was previously believed to be devoid of lymphatic structures, except for the conjunctiva. However, Lymphatic vessels have been recently identified in the cornea (under pathological conditions), limbus, ciliary body, extraocular muscles, conjunctiva, lacrimal gland, optic nerve sheath, and lymphoid structures in the choroid and Schlemm’s duct. These novel findings have significant implications in eye disease treatment; however, the mechanisms by which they preserve immune balance in the eye and eliminate metabolic waste and inflammatory cells remain nebulous. Furthermore, connections have been observed between ocular and nasal lymphatic vessels via the lymphatic network accompanying the nasolacrimal duct. The nasal lymphatic vessels are the primary pathway for cerebrospinal fluid drainage and a new route for drug delivery and treatment of brain-related diseases. This review provides an overview of recent advancements in understanding the structure and function of the ocular and nasal lymphatic systems and their association with cerebrospinal fluid drainage and various diseases.

Peer Review reports

Introduction

The lymphatic system, analogous to the blood vascular network, comprises lymphatic vessels, lymphoid organs, and lymphoid tissues and is involved in regulating fluid balance and immune surveillance [1]. Mucosa-associated lymphoid tissue is distributed along the surfaces of all mucosal membranes [2] and constitutes approximately half of the body’s immune system lymphocytes [3]. Lymphatic vessels are present in the normal nasal mucosa of the inferior turbinate, middle turbinate, and ethmoid sinus mucosa, most distributed in the superficial mucosal layer beneath the epithelium [4]. The nasal cavity has no other lymphatic vessels [5, 6].

In rodents, nasal-associated lymphoid tissue typically comprises secondary lymphoid aggregates, and, at birth, it contains small lymphoid and non-lymphoid cells. Nasal-associated lymphoid tissue also displays a helper T-cell phenotype [7], indicating a potential response to antigenic stimulation. Recently, a possible connection between nasal lymphatics and cerebrospinal fluid (CSF) drainage has been proposed [8]. Following its production, CSF flows through the cribriform plate into the nasal lymphatic vessels, subsequently draining into the deep cervical lymph nodes. Issues with the cribriform plate can lead to rhinorrhea and pose health risks. However, the pathogenesis of CSF leakage in certain cases remains unclear, necessitating further research [9, 10].

The eye, an anatomical extension of the central nervous system (CNS), is traditionally thought to lack standard drainage systems [11]. However, lymphatic vessels have recently been discovered in various anatomical structures of the eye, including the cornea (under pathological conditions), limbus, ciliary body, extraocular muscles, conjunctiva, lacrimal gland, optic nerve sheath, and lymphoid structures in the choroid and Schlemm’s duct [12, 13]. Lymphatic vessels within the optic nerve sheath can drain CSF into the deep cervical lymph nodes, indicating a shared lymphatic system with the brain [14]. The glial lymphatic system in the retina and optic nerve is involved in metabolic waste clearance and immune homeostasis maintenance in the eye. However, the interrelationships between these various mechanisms remain to be elucidated. The lymphatic system in the eye and nasal region is rich and plays essential roles in maintaining homeostasis and disease pathogenesis. In this review, we discuss the anatomy and function of ocular and nasal lymphatics, research progress, and the relationship between nasal and ocular lymphatics and CSF drainage.

Connections between the ocular and nasal lymphatics

Numerous nasal diseases impact eye health, as the eyes and nose are linked by the nasolacrimal duct (NLD). Anatomically, the eyes and nose are adjacent. A saline injection into the lacrimal punctum flows into the nasal cavity, demonstrating the structural and functional connection between the two (Fig. 1). In recent years, research into the function of the lymphatic system in immune monitoring has shown a connection between nasal lymphatic vessels and lymphatic vessels in the ocular region through the lymphatic network accompanying the NLD [5], in which lymphatic vessels of the inferior turbinate are connected to those of the eyelid and conjunctiva [6].

Fig. 1
figure 1

Anatomical relationship between the nose and eyes. The nose and eyes are connected through the nasolacrimal duct

Full size image

Smoking is the most prominent cause of exacerbated eye disease in thyroid-associated patients [15], although it is primarily exposed to the nasal and pharyngeal mucosa; however, how smoking is transmitted to the eye and causes extraocular muscle hypertrophy remains to be determined. Allergic rhinitis is associated with allergic conjunctivitis, redness of the eyes, itching, and tearing [16]. Extranodal nasal NK/T-cell lymphoma, a rare, aggressive, non-Hodgkin lymphoma outside the lymphatic system and affects the nose, occurs mainly in the nasopharynx; the clinical symptoms have also been observed in the eye, such as eyelid swelling, decreased visual acuity, and subconjunctival tumors [17, 18]. Recently, a case of extranodal nasal-type NK/T-cell lymphoma metastasizing to the eye has been reported [19]. Although how this nasal tumor metastasizes to the eye remains unclear, this illustrates a close link between the eye and the nasal lymphatic system. Treated orbital extranodal NK/T-cell lymphomas can relapse by CSF or vitreous metastasis to the contralateral eye [20]. Early symptoms of Nasopharyngeal carcinoma (NPC) may not appear in the nasal cavity and pharynx; ophthalmic symptoms, however, are caused by orbital invasion. In advanced NPC, the tumor can invade the posterior orbit through the inferior orbital fissure via the pterygopalatine fossa or extend into the cavernous sinus to infiltrate the superior orbital fissure. Invasion of the apical end, involving the optic nerve sheath and extraocular muscles, can also occur through ethmoid and sphenoid sinus spread

Ocular lymphatics

Corneal lymphatics

The cornea, a transparent avascular connective tissue, is one of the primary mediators of ocular involvement in refraction. Lymphatic vessels are typically found at the corneal limbus; healthy corneas contain no blood or lymphatic vessels. However, corneal vascularization can affect vision, while lymphatic vessel generation can affect corneal immunity and inflammation [26]. Collin [27] injected ink into the rabbit cornea and discovered that the cornea could proliferate neovascularization and produce neolymphatic vessels. Mimura et al. [28] burned rats with silver nitrate to induce corneal circumferential neovascularization and observed lymphatic vessels in the injured cornea under electron microscopy. The authors also found that VEGF-C and VEGFR-3 were endogenous factors associated with corneal lymphangiogenesis. The discovery of specific markers, such as LYVE-1, podoplanin, CCL21, FOXC2, and VEGFR-3, has advanced the study of corneal lymphatic vessels.

When the cornea is inflamed due to severe stimuli, such as infection, inflammation, or chemical burns, the production of limbal lymphatics increases, extending from the limbal region to the center of the cornea [1, 12, 29, 30]. Truong et al. [31] were the first to discover a luminal flap within a newly formed lymphatic vessel in an inflamed cornea, indicating that lymphatic drainage occurs outside the cornea, starting from the limbal region. The limbal lymphatic network gradually forms and branches from primary lymphatic vessels that grow in the medial nasal region and invade the limbus and conjunctiva, encircling the cornea in a bidirectional manner. There are more corneal lymphatic valves in the nose than in the temporal region. Additionally, lymphatic vessels are denser on the nasal side than on the temporal side [31, 32].

Corneal graft rejection, which occurs when the immune system identifies the transplanted corneal tissue as foreign and mounts an immune response against it, is the leading cause of corneal transplant failure [33]. Generating corneal lymphatic vessels may alter the immune tolerance and rejection response of the cornea, lowering the success rate of corneal transplantation [34, 35]. Notably, corneal neolymphatic vessels are generated during the development of dry eye without neovascularization. Moreover, as dry eye symptoms worsen, corneal lymphatics extend centrally, increasing in size and caliber [36, 37]. In addition to this, the VEGF family and its receptor VEGFR have been found to be critical in promoting corneal lymphangiogenesis [38, 39]. Numerous detailed studies have explored the mechanism of corneal lymphangiogenesis, making the treatment and drug discovery targeting lymphatic vessels highly significant for corneal therapy diseases [39,40,41].

Retinal lymphatics

The retina is a thin layer of tissue located at the back of the eyeball. It contains photoreceptor cells that capture light and convert it into neural signals, which are transmitted to the brain via the optic nerve to create vision. The retina is also considered an extension of the CNS. The metabolic activity in the retina is relatively high; it is rich in blood vessels but lacks lymphatic vessels. In 2012, Iliff [42] proposed the paravascular transport system that efficiently removes interplasmic solutes from the brain. This system was named the “gelatinous lymphatic system” and has similar perivascular spaces in the retina. Occlusion of these gelatinous lymphatic channels in the neuroretina not only maintains the physiological and metabolic balance of the retina but also plays a role in the drainage of aqueous humor [43, 44]. However, in 2022, Rusu et al. [45] identified lymphatic vessels in the retinal endothelial cells of rats by detecting specific markers. The authors observed a network of obtuse lympho-endothelial ducts in Wistar rat eyes embedded in paraffin using podoplanin, a lymphatic vessel marker. Nevertheless, this feature cannot be generalized to other species. It has been suggested that at least two markers are needed to identify lymphatic vessels in addition to areas where lymphatic vessels have been identified. Whether lymphatic vessels exist in rat retinal endothelial cells remains unverified [46].

Optic nerve lymphatics

The optic nerve, which transmits visual information from the eye to the brain’s visual center, extends from the back of the eyeball into the brain and connects with the CSF through the perivascular space [47]. In 1999, Killer et al. [48] identified lymphatic vessels within the optic nerve sheath using electron microscopy and immunohistochemistry. Considering that the optic nerve is an extension of the orbital CNS, CSF tracers injected into the subarachnoid space drain through the optic nerve into the periorbital tissues and cervical lymph nodes [49]. Ludemann et al. have stipulated that CSF drained through the optic nerve sheath can flow into the orbit from the subarachnoid space [50], although the mechanisms by which CSF flows into the orbit under normal intracranial pressure remain unclear. Specifically, when the intracranial pressure increases, CSF drains into conjunctival lymphatics through the optic nerve subarachnoid space. However, lymphatic vessels reside in the optic nerve sheath, not the optic nerve itself [14], and are vital for CSF drainage and waste clearance. In addition, the glymphatic system, formed by astrocytes [51, 52], is an alternative waste removal system in the eye that functions in the brain parenchyma and acts as a pathway for exchanging interstitial fluid (ISF) and CSF in the brain.

The eye and brain are part of the CNS and have traditionally been thought to lack a neural drainage system [11], although share similar physiological structures and immune responses. In 2015, Denniston et al. [53] and Wostyn et al. [52] hypothesized the existence of a glymphatic system in the eye, which could be of significance in the treatment of eye diseases, such as glaucoma and age-related macular degeneration (AMD). Supporting this hypothesis, Mathieu et al. [47] provided the first evidence of a glymphatic pathway in the optic nerve; the authors observed that molecules < 70 kDa entered the optic nerve parenchyma through the glymphatic system following injection of fluorescent dextran tracers into the CSF in mice. Recently, Wang et al. [54] observed the clearance of the tracer in the retina and vitreous through AQP4 water channels following intravitreal injections of amyloid B in mice. These findings confirm the presence of a gelatinous lymphoid system in the eye, similar to that in the brain. The oculocranial pressure gradient is a crucial driving force for these lymphatic processes. Yin et al. [14] injected fluorescently labeled dextran into the anterior chamber or vitreous cavity and confirmed that lymphatic vessels in the optic nerve sheath drained the dye into the deep cervical lymph nodes. Consequently, the authors proposed different lymphatic drainage systems for the anterior and posterior parts of the eye. Specifically, the posterior part shares lymphatic circulation with the brain through lymphatic drainage in the optic nerve sheath, creating an immune function connection with the brain. This discovery provides new possibilities for treating eye and CNS diseases.

Other ocular lymphatics

Lymphatics have been observed in the conjunctiva, extraocular muscles, lacrimal glands, ciliary body, and Schlemm’s ducts. The choroids also contain a lymphatic vasculature-like system (Fig. 2).

Fig. 2
figure 2

Eye anatomy. Red asterisks indicate structures with confirmed presence of lymphatic vessels. Green asterisks indicate structures wherein the presence or absence of lymphatic vessels remains to be confirmed. Blue asterisks indicate structures that have not yet been investigated for lymphatic vessels

Full size image

Conjunctival lymphatics

The conjunctiva, a layer of a mucosal membrane covering the upper and lower eyelids and the surface of the eyeball, is divided into the bulbar conjunctiva, palpebral conjunctiva, and fornix conjunctiva. Historically, the eye was believed to lack lymphatic vessels, with the conjunctiva being the only exception. However, more ocular tissues are now recognized to possess lymphoid structures, yet the conjunctiva remains the primary site for lymphatic vessels in the eye [26]. In 2003, Singh et al. demonstrated the presence of conjunctival lymphatics using subconjunctival injection of trypan blue; the authors divided them into two layers: superficial fine lymphatics and deep, thicker lymphatics [55]. Knop et al. [56, 57] referred to the ocular lymphatic system as eye-related lymphoid tissue, which includes the lacrimal gland, conjunctiva-associated lymphoid tissue, and lacrimal gland drainage-associated lymphoid tissue. Conjunctiva-associated lymphoid tissue is divided into a diffuse lymphoid layer, follicles, and interfollicular crypt-associated lymphoid tissue, an immunocompetent interface that plays an important role in regulating ocular surface inflammation, immune response, and chronic ocular surface diseases, although the underlying mechanism remains nebulous [58, 59]. Yu et al. [60] confirmed that the conjunctival lymphatics can clear ISF and reabsorb the aqueous humor following filtration surgery, reducing intraocular hypertension in glaucoma. In addition, conjunctival lymphatic vessels are involved in the pathogenesis of pterygium and conjunctivochalasis; the incidence rate of these diseases is related to the degree of conjunctival lymphangiogenesis or dilatation. Therefore, targeting conjunctival lymphatic vessels is a potential treatment strategy that warrants further research [61, 62].

Extraocular muscle lymphatics

The presence of lymphatics in extraocular muscles remains controversial. Damasceno et al. [63] and Philips et al. [64] performed podoplanin immunohistochemical staining of unilateral orbital muscles from fresh human cadavers and reported differed results. Damasceno et al. [63] concluded that lymphatic vessels were present in the connective tissue of all extraocular muscles. In contrast, Philips et al. [64] found no lymphatic vessels in any extraocular muscle but identified some close to the anterior part of the levator muscle. Notably, both T and B cells were present in all extraocular muscles examined. The discrepancies among these findings may stem from differences in tissue sampling sites or race and age. Additionally, it is plausible that lymphatic vessels in extraocular muscles are present only in the connective tissue. Philips et al. [64] did not mention whether their muscle samples included connective tissue. Therefore, further experimental verification is needed to determine the presence and location of lymphatic vessels in extraocular muscles.

Lacrimal gland lymphatics

Sherman et al. [65] and Gausas et al. [66] identified lymphatic vessels in the lacrimal gland through enzymatic histochemical staining and morphological analysis using electron microscopy. These findings were validated via immunohistochemical staining for podoplanin by Damasceno et al. [63]. Importantly, the findings are crucial for studying lacrimal gland-related immune diseases.

Ciliary body lymphatics

In 2009, Yucel et al. [67] used LYVE-1 and podoplanin to stain human ocular tissues, confirmed the presence of lymphatic vessels in the ciliary body of normal eyes using various imaging techniques, and found that the uveal lymphatic pathway could drain aqueous humor, making them the first to confirm this phenomenon. Subsequently, the Heindl et al. [68] confirmed the presence of lymphatic vessels in the ciliary body of melanomas containing extraocular dilatation.

Schlemm’s Canal lymphatics

Schlemm’s canal, discovered by the German anatomist Friedrich Schlemm in 1830, is a unique endothelial vessel in the eye that is considered a hybrid of lymphatic and blood vessels [69]. This canal maintains intraocular pressure by facilitating the drainage of aqueous humor in conjunction with the trabecular meshwork, clearing out bacteria, foreign particles, and other waste products from the ocular surface [70].

Choroid lymphatics

The existence of true lymphatic vessels in the choroid remains controversial. In 1988, Krebs et al. [71] reported lymphatic-like features in the choroid of non-human primates. Subsequent studies using lymphatic-specific staining on the choroids of adult and fetal human eyes suggested the presence of pre-lymphatic channels; however, the specific pathway connecting the eye to sentinel lymph nodes remaines unclear [72].

In the same year, Schrödl et al. [73] conducted lymphatic marker assays on frozen sections of human choroids but detected no classical lymphatic vessels. Therefore, the presence of lymphatic vessels in the choroid remains to be verified. This inconsistency necessitates further research to elucidate the presence and function of lymphatic structures in ocular tissues. Such discoveries will provide novel insights into ocular immune mechanisms and facilitate the development of new therapeutic strategies for eye diseases.

Diseases associated with the ocular lymphatics

Although the eye has been thought to lack lymphatic vessels, evidence confirms the ocular lymphatic system, connecting the eye to the immune system. This discovery has improved the diagnosis and treatment of various ocular diseases, including glaucoma, a blinding eye disease caused by increased intraocular pressure due to inadequate drainage of aqueous humor.

Researchers have recently identified intraocular lymphatics as a potential target for glaucoma treatment. Yucel et al. conducted studies in sheep using fluorescence tracing and radiotracing and found that markers drained faster through the uveal lymphatic pathway than the conventional route [67]. Neolymphangiogenesis, the formation of new lymphatic vessels, in the cornea can impact the development of dry eye and the success rate of corneal transplantation. Anti-corneal lymphangiogenesis therapy plays a significant role in the treatment of corneal diseases [34, 38].Additionally, microRNAs, which negatively regulate gene expression, inhibit corneal lymphangiogenesis, with microRNA-184 being particularly interesting [74]. Studies on the ocular lymphatic system have also revealed the potential of microRNA-184 in guiding research and treatment for CNS diseases, such as Alzheimer’s disease (AD) and multiple sclerosis. These diseases arise from increased tau protein concentration in CSF and the abnormal accumulation of amyloid beta (Aβ) plaques [75]. Optic nerve sheath lymphatic vessels and the gelatinous lymphatic system play a role in draining CSF and removing soluble interstitial Aβ from the brain, thereby maintaining CSF balance [76]. AMD and AD have similar characteristics, are more common with age, and are associated with amyloid deposition [77]. This suggests that the gelatinous lymphatic system in the retina may be crucial in treating AMD and other retinal diseases. Furthermore, a better understanding of the structure and function of the ocular lymphatic system can aid in developing novel drug delivery systems. By targeting the ocular lymphatic system, drugs can be delivered more effectively to treat various ocular diseases.

Nasal mucous lymphatics

Structure and lymphatics of the nasal mucosa

The nasal mucosa is a protective and functional barrier comprising mucosal tissue that covers the interior of the nasal cavity and serves as the immune system’s first line of defense against invading pathogens [78]. Within this mucosal tissue, a well-developed lymphatic network has been identified.

Hoseman et al. [79] confirmed the presence of lymphatic vessels in the nasal mucosa in sampling studies of patients with chronic sinusitis. Specifically, lymphatic vessels are present in the middle and inferior turbinate mucosa and normal ethmoid mucosa [4]. Notably, the vomeronasal organ’s mucosa and inferior turbinate contain abundant lymphatic vessels, with connections between the inferior turbinate and those of the eyelid and conjunctiva [6]. Furthermore, the lymphatic vessels of the sphenoid mucosa of the paranasal sinuses are connected to pharyngeal lymphatic vessels [5, 6]. Therefore, an ISF outflow pathway is formed from the eye, NLD, nose, pharynx, and deep cervical lymph. These lymphatic pathways exclude ISF and transport immune cells and waste products.

Nasal lymphatics and CSF drainage

CSF maintains brain tissue homeostasis, detects immune cells, and removes metabolic waste [80,81,82]. CSF accesses cervical lymph nodes via lymphatics and affects the clearance of brain molecules [83], possibly related to nervous system-related lesions. However, understanding the mechanisms by which CSF drains to lymph nodes through lymphatic vessels has been challenging [8].

The main CSF drainage routes from the subarachnoid space are the cribriform plate (Fig. 3) and the peripheral cranial nerves [24, 25]. Several studies are currently exploring CSF drainage through the nasal lymphatic vessels. Injection of radio-iodinated albumin and India ink into the cisterns of rabbits and mice, respectively, showed that the nasal mucosa was the only channel for intracranial CSF to enter the deep cervical lymphatic vessels [84, 85]. Johnston et al. [86] injected Microfil into the CSF compartment of six animal species and humans and traced it in the olfactory bulb and cribriform plate, providing the first evidence of human CSF draining into the nasal lymphatic vessels. In addition, the tracer was found in the deep cervical lymph nodes shortly following injection. Therefore, some scholars have proposed a direct connection between mucosal lymphatic vessels and CSF [86, 87].

Fig. 3
figure 3

Two pathways for CSF drainage [1]. First nasopharyngeal lymphatic pathway: CSF originates from choroidal plexus (black arrow ①), passes through the cribriform plate into the nasopharyngeal lymphatic plexus (black arrow ③ ④), and drains into the deep cervical lymph nodes (black arrow ⑤) [2]. Second ocular lymphatic pathway: CSF originates from choroidal plexus(purple arrow), CSF influx (blue arrow), CSF-ISF exchange (blue gradient arrow), and finally drains into the deep cervical lymph nodes (green arrow). CSF, Cerebrospinal fluid; ISF, interstitial fluid

Full size image

A more recent study performed magnetic resonance imaging following subthecal injection of gadobutrol and found higher accumulation near the cribriform plate and lesser accumulation in the nasal mucosa or septum lymph [88]. This finding raises questions regarding the importance of lymphatic drainage of CSF from the nasal mucosa. However, other studies using a fluorescent CSF tracer technique have demonstrated the role of nasopharyngeal lymphatics in CSF outflow [8, 89, 90].

The nasopharyngeal lymphatic plexus may atrophy with age, yet signaling pathways such as adrenergic, nitric oxide, and prostaglandin analog transduction can enhance CSF outflow, increasing CSF clearance in age-related diseases [8, 91]. Furthermore, lymphatic vessels are abundant in the ethmoid bone, and the cribriform plate serves as a bridge between CSF and peripheral lymphatic vessels [92,93,94]. In this system, CSF flows through the cribriform plate and is absorbed by lymphatic vessels in the nasal mucosa, facilitating its transport to the cervical lymph nodes. Therefore, complications with the ethmoid sinuses, where CSF leaks and fails to drain normally through lymphatic vessels to the deep cervical lymph nodes, can cause watery nasal discharge [10, 95].

Maintaining normal CSF flow from the brain is thus crucial not only for neurological health but also for supporting immune functions and overall health.

Nasal lymphatics and associated diseases

Lymphatic vessels form a dense vascular network that supplies oxygen and nutrients while removing metabolic waste products and are a critical component of the immune system, maintaining tissue fluid homeostasis and offering sites for antigen presentation and immune activation. Dysfunction in lymphatic drainage is associated with infection, chronic inflammation, and cancer metastasis, and numerous other diseases [96,97,98]. For instance, the absolute and relative densities of lymphatic vessels in the nasal cavity are linked to chronic sinusitis with and without nasal polyps. Moreover, in chronic sinusitis with nasal polyps, lymphatic vessels often have low absolute and relative densities in the inferior turbinate and maxillary sinus [79]. Similarly, reduced lymphatic distribution is observed in patients with severe asthma [99]. This phenomenon is paralleled by reduced lymphatic distribution in patients with fatal asthma [100]. Conversely, higher lymphatic vessel densities are associated with the recurrence of nasal polyps [99]. Therefore, further studies to control lymphatic vessel generation and reduce their effect on disease treatment are needed.

The nasal lymphatics connected to the subarachnoid space is a novel route for infection and transmission of bacterial meningitis. This explains the negative blood cultures observed during meningitis inflammation and highlights the important role of nasal lymphatic vessels in developing this disease [101]. However, the delivery of most cancer drugs to the brain is hindered by the blood–brain barrier (BBB), limiting the treatment options for certain brain tumors. However, Semyachkina-Glushkovskaya et al. [102] demonstrated that liposomes administered through the intranasal route to mice can reach glioblastoma. Additionally, stimulation with near-infrared light (1,267 nm) can regulate the relaxation and permeability of lymphatic vessels in the cribriform plate and meningeal region, enhancing the intranasal delivery of liposomes into the brain. TTCM2, a novel antibody that can recognize toxic tau oligomers, can break through the barrier of the BBB with nasal spray and quickly enter various parts of the brain through the naso–brain pathway, reducing the cognitive function and memory of AD patients or elderly mice [103]. Overall, nasal lymphatic vessels require more attention when treating diseases.

Conclusion

The lymphatic vessels in the eye and nose remain a research hot spot, focusing on CSF drainage in these areas. Research has focused on the presence of lymphatic vessels in an increasing number of ocular structures, reshaping our understanding of the eye and ocular immune clearance. The modulation of ocular lymphatic vessels and exploration of novel therapeutic targets offer new ideas for treating glaucoma, optic nerve diseases, AMD, and corneal transplantation, among other diseases. These nasal lymphatic vessels are crucial pathways for CSF outflow and play a vital role in infection and disease transmission, as well as facilitating drug delivery to the brain through intranasal administration. These findings reveal novel strategies for therapy and drug delivery. Further in-depth research on ocular and nasal lymphatic vessels remains essential to establish a theoretical basis for understanding the occurrence, development, and pathogenic mechanisms of diseases related to the eye and nose.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

ISF:

Interstitial fluid

ENKTCL:

Extranodal natural killer/T-cell lymphoma, nasal type

NLD:

Nasolacrimal duct

AD:

Alzheimer’s disease

Aβ:

Amyloid beta

AMD:

Age-related macular degeneration

NPC:

Nasopharyngeal carcinoma

BBB:

Blood–brain barrier

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Funding

This work was supported by the Open Project of the National Facility for Translational Medicine (Shanghai) (TMSK02021-103), the Fundamental Research Funds for the Central Universities (No. YG2023ZD17), and the Department of Science and Technology of Sichuan Province, China (2020YFSY0044).

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  1. Min Yan and LuCheng contributed equally to the work and are, therefore, co-first authors.

Authors and Affiliations

  1. Eye School of Chengdu, University of Traditional Chinese Medicine, Chengdu, Sichuan, China

    Min Yan & Hui Chen

  2. Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lu Cheng, Zheng Zheng & Hui Chen

  3. National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lu Cheng, Zheng Zheng & Hui Chen

  4. University of Shanghai for Science and Technology, Shanghai, China

    Yuanxi Lin, Doudou Qin & Hui Chen

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Contributions

M.Y. and L.C. contributed equally and are co-first authors.M.Y., H.C., and L.C. contributed to the conception and design of this review.M.Y., H.C., and L.C. wrote the main manuscript.Z.Z. prepared Figs. 1 and 2.Y.X.L and D.D.Q prepared Fig. 3.All authors approved the final manuscript.

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Correspondence to Hui Chen.

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Yan, M., Cheng, L., Zheng, Z. et al. Advances in the Understanding of ocular and nasal lymphatics. BMC Immunol 26, 16 (2025). https://doi.org/10.1186/s12865-025-00697-5

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