Neutrophil Interactions with the Lymphatic System

The lymphatic system is a complex network of lymphatic vessels and lymph nodes designed to balance fluid homeostasis and facilitate host immune defence. Neutrophils are rapidly recruited to sites of inflammation to provide the first line of protection against microbial infections. The traditional view of neutrophils as short-lived cells, whose role is restricted to providing sterilizing immunity at sites of infection, is rapidly evolving to include additional functions at the interface between the innate and adaptive immune systems. Neutrophils travel via the lymphatics from the site of inflammation to transport antigens to lymph nodes. They can also enter lymph nodes from the blood by crossing high endothelial venules. Neutrophil functions in draining lymph nodes include pathogen control and modulation of adaptive immunity. Another facet of neutrophil interactions with the lymphatic system is their ability to promote lymphangiogenesis in draining lymph nodes and inflamed tissues. In this review, we discuss the significance of neutrophil migration to secondary lymphoid organs and within the lymphatic vasculature and highlight emerging evidence of the neutrophils’ role in lymphangiogenesis.

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Extracellular bacterial lymphatic metastasis drives Streptococcus pyogenes systemic infection

Nature Communications ◽

10.1038/s41467-020-18454-0 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Matthew K. Siggins ◽

Nicola N. Lynskey ◽

Lucy E. Lamb ◽

Louise A. Johnson ◽

Kristin K. Huse ◽

...

Keyword(s):

Lymph Nodes ◽

Cancer Cells ◽

Streptococcus Pyogenes ◽

Lymphatic System ◽

Lymphatic Vessels ◽

Systemic Infection ◽

Intracellular Pathogen ◽

Infection Site ◽

Local Infection ◽

Draining Lymph Nodes

Abstract Unassisted metastasis through the lymphatic system is a mechanism of dissemination thus far ascribed only to cancer cells. Here, we report that Streptococcus pyogenes also hijack lymphatic vessels to escape a local infection site, transiting through sequential lymph nodes and efferent lymphatic vessels to enter the bloodstream. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and then efferent lymphatics that carry the bacteria through successive draining lymph nodes. We identify streptococcal virulence mechanisms important for bacterial lymphatic dissemination and show that metastatic streptococci within infected lymph nodes resist and subvert clearance by phagocytes, enabling replication that can seed intense bloodstream infection. The findings establish the lymphatic system as both a survival niche and conduit to the bloodstream for S. pyogenes, explaining the phenomenon of occult bacteraemia. This work provides new perspectives in streptococcal pathogenesis with implications for immunity.

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Infrared fluorescence lymphography in experimental and clinical practice

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2018-17-2-84-91 ◽

2018 ◽

Vol 17 (2) ◽

pp. 84-91 ◽

Cited By ~ 1

Author(s):

G. V. Papayan ◽

A. L. Akopov ◽

P. A. Antonyan ◽

A. A. Ilin ◽

N. N. Petrishchev

Keyword(s):

Lymph Nodes ◽

Near Infrared ◽

Lymphatic System ◽

Lymphatic Vessels ◽

Diagnostic System ◽

Biological Tissues ◽

Peritumoral Injection ◽

Intradermal Administration ◽

Nir Fluorescence ◽

Real Time Visualization

Introduction. Near infrared (NIR) fluorescent diagnostics is promising due to a deeper penetration into biological tissues. Material and methods. In experiments on rabbits and in clinical studies evaluation the lymphatic system with the use of the instrument complex FLUM-808 was analysed. Results. For visualization of the lymphatic vessels of the skin, the intradermal administration of ICG, dissolved in 20 % albumin in the order of 0.02 mg/ml, is optimal. Peritumoral injection of ICG allows visualizing sentinel lymph nodes in patients with lung cancer. Conclusions. The developed NIR fluorescence diagnostic system FLUM-808 allows to real time visualization of lymphatic vessels and lymph nodes.

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Mast cell–derived particles deliver peripheral signals to remote lymph nodes

Journal of Experimental Medicine ◽

10.1084/jem.20090805 ◽

2009 ◽

Vol 206 (11) ◽

pp. 2455-2467 ◽

Cited By ~ 115

Author(s):

Christian A. Kunder ◽

Ashley L. St. John ◽

Guojie Li ◽

Kam W. Leong ◽

Brent Berwin ◽

...

Keyword(s):

Drug Delivery ◽

Mast Cell ◽

Mast Cells ◽

Tumor Necrosis Factor ◽

Lymph Nodes ◽

Tumor Necrosis ◽

Lymphatic Vessels ◽

Lymphoid Tissues ◽

Draining Lymph Nodes ◽

Necrosis Factor

During infection, signals from the periphery are known to reach draining lymph nodes (DLNs), but how these molecules, such as inflammatory cytokines, traverse the significant distances involved without dilution or degradation remains unclear. We show that peripheral mast cells, upon activation, release stable submicrometer heparin-based particles containing tumor necrosis factor and other proteins. These complexes enter lymphatic vessels and rapidly traffic to the DLNs. This physiological drug delivery system facilitates communication between peripheral sites of inflammation and remote secondary lymphoid tissues.

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SS9-6 In vivo imaging of high endothelial venules and lymphatic vessels in lymph nodes and tertiary lymphoid organs

Cytokine ◽

10.1016/j.cyto.2010.07.320 ◽

2010 ◽

Vol 52 (1-2) ◽

pp. 77

Author(s):

Nancy H. Ruddle ◽

Lucy A. Truman ◽

Kevin L. Bentley.

Keyword(s):

Lymph Nodes ◽

In Vivo Imaging ◽

Lymphatic Vessels ◽

Lymphoid Organs ◽

High Endothelial Venules

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Lymphangiogenesis in development and disease

Thrombosis and Haemostasis ◽

10.1160/th07-04-0238 ◽

2007 ◽

Vol 98 (08) ◽

pp. 304-310 ◽

Cited By ~ 27

Author(s):

Ruediger Liersch ◽

Michael Detmar

Keyword(s):

Lymph Nodes ◽

Cancer Metastasis ◽

Lymphatic System ◽

Vascular System ◽

Malignant Tumors ◽

Inflammatory Diseases ◽

Transplant Rejection ◽

Lymphatic Vessels ◽

Lipid Uptake ◽

Molecular Control

SummaryThe lymphatic vascular system plays an important role in the maintenance of fluid homeostasis, in the afferent immune response, in the intestinal lipid uptake and in the metastatic spread of malignant cells. The recent discovery of specific markers and growth factors for lymphatic endothelium and the establishment of genetic mouse models with impairment of lymphatic function have provided novel insights into the molecular control of the lymphatic system in physiology and in embryonic development. They have also identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. Moreover, the lymphatic system plays a major role in chronic inflammatory diseases and in transplant rejection. Importantly, malignant tumors can directly promote lymphangiogenesis within the primary tumor and in draining lymph nodes, leading to enhanced cancer metastasis to lymph nodes and beyond. Based upon these findings, novel therapeutic strategies are currently being developed that aim at inhibiting or promoting the formation and function of lymphatic vessels in disease.

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Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration

eLife ◽

10.7554/elife.42762 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 14

Author(s):

Michael RM Harrison ◽

Xidi Feng ◽

Guqin Mo ◽

Antonio Aguayo ◽

Jessi Villafuerte ◽

...

Keyword(s):

Coronary Artery ◽

Lymphatic System ◽

Vascular System ◽

Heart Function ◽

Lymphatic Vessels ◽

Adult Zebrafish ◽

Heart Patients ◽

Scar Size ◽

Lymphatic Vasculature ◽

Zebrafish Heart

The cardiac lymphatic vascular system and its potentially critical functions in heart patients have been largely underappreciated, in part due to a lack of experimentally accessible systems. We here demonstrate that cardiac lymphatic vessels develop in young adult zebrafish, using coronary arteries to guide their expansion down the ventricle. Mechanistically, we show that in cxcr4a mutants with defective coronary artery development, cardiac lymphatic vessels fail to expand onto the ventricle. In regenerating adult zebrafish hearts the lymphatic vasculature undergoes extensive lymphangiogenesis in response to a cryoinjury. A significant defect in reducing the scar size after cryoinjury is observed in zebrafish with impaired Vegfc/Vegfr3 signaling that fail to develop intact cardiac lymphatic vessels. These results suggest that the cardiac lymphatic system can influence the regenerative potential of the myocardium.

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Lymphatic Vessels and High Endothelial Venules are Increased in the Sentinel Lymph Nodes of Patients with Oral Squamous Cell Carcinoma Before the Arrival of Tumor Cells

Annals of Surgical Oncology ◽

10.1245/s10434-011-2154-9 ◽

2011 ◽

Vol 19 (5) ◽

pp. 1595-1601 ◽

Cited By ~ 24

Author(s):

Man Ki Chung ◽

In-Gu Do ◽

Eunwook Jung ◽

Young-Ik Son ◽

Han-Sin Jeong ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Lymph Nodes ◽

Cell Carcinoma ◽

Tumor Cells ◽

Squamous Cell ◽

Lymphatic Vessels ◽

Sentinel Lymph Nodes ◽

High Endothelial Venules

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Sulfation-dependent recognition of high endothelial venules (HEV)-ligands by L-selectin and MECA 79, and adhesion-blocking monoclonal antibody.

Journal of Experimental Medicine ◽

10.1084/jem.180.6.2219 ◽

1994 ◽

Vol 180 (6) ◽

pp. 2219-2226 ◽

Cited By ~ 195

Author(s):

S Hemmerich ◽

E C Butcher ◽

S D Rosen

Keyword(s):

Monoclonal Antibody ◽

Lymph Node ◽

Lymph Nodes ◽

Lymphoid Organs ◽

Metabolic Inhibitor ◽

Dependent Manner ◽

Independent Molecule ◽

High Endothelial Venules ◽

Additional Ligand ◽

Secondary Lymphoid Organs

L-selectin is a lectin-like receptor that mediates the attachment of lymphocytes to high endothelial venules (HEV) of lymph nodes during the process of lymphocyte recirculation. Two sulfated, mucin-like glycoproteins known as Sgp50/GlyCAM-1 and Sgp90/CD34 have previously been identified as HEV-associated ligands for L-selectin. These proteins were originally detected with an L-selectin/Ig chimera called LEC-IgG. GlyCAM-1 and CD34 are also recognized by an antiperipheral node addressin (PNAd) mAb called MECA 79, which blocks L-selectin-dependent adhesion and selectively stains lymph node HEV. The present study compares the requirements for the binding of MECA 79 and LEC-IgG to HEV-ligands. Whereas desialylation of GlyCAM-1 and CD34 drastically reduced binding to LEC-IgG, this treatment enhanced the binding of GlyCAM-1 to MECA 79. In contrast, the binding of both MECA 79 and LEC-IgG to GlyCAM-1 and CD34 was greatly decreased when the sulfation of these ligands was reduced with chlorate, a metabolic inhibitor of sulfation. Because MECA 79 stains HEV-like vessels at various sites of inflammation, recognition by L-selectin of ligands outside of secondary lymphoid organs may depend on sulfation. In addition to their reactivity with GlyCAM-1 and CD34, both MECA 79 and LEC-IgG recognize an independent molecule of approximately 200 kD in a sulfate-dependent manner. Thus, this molecule, which we designate Sgp200, is an additional ligand for L-selectin.

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Infection-Induced Dermal Lymphatic Zippering Restricts Viral Dissemination from Skin and Promotes Anti-Viral CD8+ T Cell Expansion

10.1101/2021.08.26.457551 ◽

2021 ◽

Author(s):

Madeline J. Churchill ◽

Haley du Bois ◽

Taylor A. Heim ◽

Tenny Mudianto ◽

Maria M. Steele ◽

...

Keyword(s):

T Cell ◽

Lymph Nodes ◽

Vaccinia Virus ◽

Host Defense ◽

Lymphatic Vessels ◽

T Cell Responses ◽

Lymphatic Capillary ◽

Viral Dissemination ◽

Cell Responses ◽

Draining Lymph Nodes

AbstractLymphatic vessels are often considered passive conduits that rapidly flush antigenic material, pathogens, and cells to draining lymph nodes. Recent evidence, however, suggests that lymphatic vessels actively regulate diverse processes from antigen transport to leukocyte trafficking and dietary lipid absorption. Here we tested the hypothesis that dermal lymphatic transport is dynamic and contributes to innate host defense during viral infection. We demonstrate that cutaneous vaccinia virus infection activates the tightening of lymphatic interendothelial junctions, termed zippering, in a VEGFA/VEGFR2-dependent manner. Both antibody-mediated blockade of VEGFA/VEGFR2 and lymphatic-specific deletion of Vegfr2 impaired lymphatic capillary zippering and increased fluid flux out of tissue. Strikingly, inhibition of lymphatic zippering allows viral dissemination to draining lymph nodes independent of dendritic cell migration and impairs CD8+ T cell priming. These data indicate that infection-induced dermal lymphatic capillary zippering is a context-dependent, active mechanism of innate host defense that limits interstitial fluid and virion flux and promotes protective, anti-viral CD8+ T cell responses.SummaryCutaneous infection with vaccinia virus induces VEGFR2-dependent dermal lymphatic capillary zippering. This tightening of lymphatic junctions exacerbates tissue edema, sequesters virus, and promotes anti-viral CD8+ T cell responses. Dermal lymphatic capillaries are therefore an active component of innate host defense.

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