Current concepts on communication between the central nervous system and peripheral immunity via lymphatics: what roles do lymphatics play in brain and spinal cord disease pathogenesis?

Hsu, Martin; Sándor, Mátyás; Fábry, Zsuzsanna

doi:10.1007/s42977-021-00066-4

Cited by 12 publications

(14 citation statements)

References 114 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nevertheless, recent studies have highlighted a role for all of these meningeal lymphatics in fluid drainage, with some suggesting that the primary route of drainage is through lymphatics instead of venous routes such as through arachnoid villi or granulations and into dural veins ( Ma et al, 2017 ). For a general overview and historical context for current hypotheses of CSF efflux routes, we cite recent reviews by our lab ( Hsu et al, 2021 ) and/or Steven Proulx (2021) . A detailed list of studies investigating CSF efflux routes prior to 2005 is reviewed by Miles Johnston ( Koh et al, 2005 ), and here we summarize more current CSF efflux studies since 2005 ( Table 1 ).…”

Section: Do Cns Lymphatics Have Access To Csf?mentioning

confidence: 99%

“…Brain lymphatics were shown for the first time in 1787 by Mascagni ( Sandrone et al, 2019 ; Hsu et al, 2021 ; Proulx, 2021 ). Since the 1800s, several studies were aimed at characterizing the drainage pathways from the central nervous system (CNS) in which parallels were drawn between the subarachnoid space surrounding the brain and lymphatics in the periphery ( Rodriguez-Peralta, 1957 ; Földi et al, 1966 ; Andres et al, 1987 ; Cserr et al, 1992b ; Kida et al, 1993 ; Bozanovic-Sosic et al, 2001 ; Mollanji et al, 2001b ; Koh et al, 2005 ; Pollay, 2010 ; Weller et al, 2010 ; Laman and Weller, 2013 ; Brøchner et al, 2015 ; Engelhardt et al, 2017 ; Hannocks et al, 2018 ; Castro Dias et al, 2019 ).…”

Section: Introduction and Significance Of Lymphaticsmentioning

confidence: 99%

See 1 more Smart Citation

Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases

Hsu

Laaker

Sándor

et al. 2021

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

The central nervous system (CNS) undergoes immunosurveillance despite the lack of conventional antigen presenting cells and lymphatic vessels in the CNS parenchyma. Additionally, the CNS is bathed in a cerebrospinal fluid (CSF). CSF is continuously produced, and consequently must continuously clear to maintain fluid homeostasis despite the lack of conventional lymphatics. During neuroinflammation, there is often an accumulation of fluid, antigens, and immune cells to affected areas of the brain parenchyma. Failure to effectively drain these factors may result in edema, prolonged immune response, and adverse clinical outcome as observed in conditions including traumatic brain injury, ischemic and hypoxic brain injury, CNS infection, multiple sclerosis (MS), and brain cancer. Consequently, there has been renewed interest surrounding the expansion of lymphatic vessels adjacent to the CNS which are now thought to be central in regulating the drainage of fluid, cells, and waste out of the CNS. These lymphatic vessels, found at the cribriform plate, dorsal dural meninges, base of the brain, and around the spinal cord have each been implicated to have important roles in various CNS diseases. In this review, we discuss the contribution of meningeal lymphatics to these processes during both steady-state conditions and neuroinflammation, as well as discuss some of the many still unknown aspects regarding the role of meningeal lymphatics in neuroinflammation. Specifically, we focus on the observed phenomenon of lymphangiogenesis by a subset of meningeal lymphatics near the cribriform plate during neuroinflammation, and discuss their potential roles in immunosurveillance, fluid clearance, and access to the CSF and CNS compartments. We propose that manipulating CNS lymphatics may be a new therapeutic way to treat CNS infections, stroke, and autoimmunity.

show abstract

Section: Do Cns Lymphatics Have Access To Csf?mentioning

confidence: 99%

Section: Introduction and Significance Of Lymphaticsmentioning

confidence: 99%

Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases

Hsu

Laaker

Sándor

et al. 2021

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Visualization of India ink penetration reveals an explicit egress pathway for CSF into the nasal mucosa (Lowhagen et al, 1994). Post-mortem analysis of fluid dynamics in the olfactory region using India ink by Lowhagen Ultimately, the detection of α-synuclein aggregation is comparable to corpuscle aggregation in olfactory mucosa and deepens our understanding of the physiological and pathological relevance of fluid drainage across the brain-nose interface (Hsu et al, 2021a). Characterization of CSF drainage through the nasal mucosa was first examined in Johnston et al, whose experimental design utilized MicroFil injections into the subarachnoid space across a variety of species (described above).…”

Section: Post-mortem Human Studiesmentioning

confidence: 99%

“…RT-QuIC, real-time quaking-induced conversion, detection of α-synuclein aggregates displayed a mucosal positivity of 44.4% for RBD patients, 46.3% for Parkinson’s patients, and 10.2% for control subjects ( Stefani et al, 2021 ). Ultimately, the detection of α-synuclein aggregation is comparable to corpuscle aggregation in olfactory mucosa and deepens our understanding of the physiological and pathological relevance of fluid drainage across the brain-nose interface ( Hsu et al, 2021a ).…”

Section: Post-mortem Human Studiesmentioning

confidence: 99%

The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans

Mehta

Sherbansky²,

Kamer³

et al. 2022

Front. Physiol.

View full text Add to dashboard Cite

The human brain functions at the center of a network of systems aimed at providing a structural and immunological layer of protection. The cerebrospinal fluid (CSF) maintains a physiological homeostasis that is of paramount importance to proper neurological activity. CSF is largely produced in the choroid plexus where it is continuous with the brain extracellular fluid and circulates through the ventricles. CSF movement through the central nervous system has been extensively explored. Across numerous animal species, the involvement of various drainage pathways in CSF, including arachnoid granulations, cranial nerves, perivascular pathways, and meningeal lymphatics, has been studied. Among these, there is a proposed CSF clearance route spanning the olfactory nerve and exiting the brain at the cribriform plate and entering lymphatics. While this pathway has been demonstrated in multiple animal species, evidence of a similar CSF egress mechanism involving the nasal cavity in humans remains poorly consolidated. This review will synthesize contemporary evidence surrounding CSF clearance at the nose-brain interface, examining across species this anatomical pathway, and its possible significance to human neurodegenerative disease. Our discussion of a bidirectional nasal pathway includes examination of the immune surveillance in the olfactory region protecting the brain. Overall, we expect that an expanded discussion of the brain-nose pathway and interactions with the environment will contribute to an improved understanding of neurodegenerative and infectious diseases, and potentially to novel prevention and treatment considerations.

show abstract

“…The network of lymphatic vessels residing in the meninges surrounding the central nervous system (CNS) have been characterized, and drainage of fluid and macromolecules through these lymphatic vessels has been studied during steady-state conditions [1][2][3][4] ; 5 . Because meningeal lymphatics are hypothesized to facilitate drainage of CSF, they have also been shown to play significant roles in pathology where drainage of excess fluid, cells, and/or antigens are critical, including experimental autoimmune encephalomyelitis (EAE) 4,6 , glioblastoma [7][8][9] , Alzheimer's disease 10 , aging 10,11 , Parkinson's disease 12 , stroke 13 , cerebrovascular disease 14 , and several other models 15 . Global inhibition of meningeal lymphatic function using the VEGFR3 tyrosine kinase inhibitor MAZ51 or locally using photoablation prior to EAE onset can reduce CNS-derived autoantigen drainage and delay EAE onset 4,6 , worsens pathology in a mouse model of Alzheimer's disease 10 , and in traumatic brain injury 16 .…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammation creates an immune regulatory niche at the meningeal lymphatic vasculature near the cribriform plate.

Fábry

Hsu

Laaker

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Meningeal lymphatic vessels residing in the dural layer above the sinuses of the brain, meninges at the base of the brain, and near the cribriform plate have all been shown to drain fluid, cells, and antigens. We have previously reported that meningeal lymphatics near the cribriform plate undergo VEGFR3-dependent lymphangiogenesis during experimental autoimmune encephalomyelitis (EAE) to facilitate excess drainage. Using single-cell RNA sequencing (scRNA-seq), we report that neuroinflammation changes the phenotype and function of cribriform plate lymphatic endothelial cells (cpLECs). Upregulation of genes involved in antigen presentation, adhesion to leukocytes, and immunoregulatory molecules were verified by flow cytometry and functional assays. The inflamed cpLECs retain dendritic cells and to lesser extent CD4 T cells, creating an immune-regulatory niche that represents a previously underappreciated interface in the regulation of neuroinflammation. Additionally, the discontinuity of the arachnoid membrane near cpLECs provides unrestricted access to the cerebrospinal fluid (CSF) for immune surveillance. These findings may lead to new therapeutic approaches to neuroinflammatory diseases.

show abstract

Current concepts on communication between the central nervous system and peripheral immunity via lymphatics: what roles do lymphatics play in brain and spinal cord disease pathogenesis?

Cited by 12 publications

References 114 publications

Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases

Neuroinflammation-Driven Lymphangiogenesis in CNS Diseases

The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans

Neuroinflammation creates an immune regulatory niche at the meningeal lymphatic vasculature near the cribriform plate.

Contact Info

Product

Resources

About