scholarly journals Dendritic cell entry to lymphatic capillaries is orchestrated by CD44 and the hyaluronan glycocalyx

2021 ◽  
Vol 4 (5) ◽  
pp. e202000908
Author(s):  
Louise A Johnson ◽  
Suneale Banerji ◽  
B Christoffer Lagerholm ◽  
David G Jackson
Keyword(s):  
Lymph Nodes ◽  
Gene Knockout ◽  
Lymphatic Vessels ◽  
Skin Inflammation ◽  
Vital Role ◽  
Cell Entry ◽  
Peripheral Tissues ◽  
Weak Binding ◽  
Endothelial Receptor

DCs play a vital role in immunity by conveying antigens from peripheral tissues to draining lymph nodes, through afferent lymphatic vessels. Critical to the process is initial docking to the lymphatic endothelial receptor LYVE-1 via its ligand hyaluronan on the DC surface. How this relatively weak binding polymer is configured for specific adhesion to LYVE-1, however, is unknown. Here, we show that hyaluronan is anchored and spatially organized into a 400–500 nm dense glycocalyx by the leukocyte receptor CD44. Using gene knockout and by modulating CD44-hyaluronan interactions with monoclonal antibodies in vitro and in a mouse model of oxazolone-induced skin inflammation, we demonstrate that CD44 is required for DC adhesion and transmigration across lymphatic endothelium. In addition, we present evidence that CD44 can dynamically control the density of the hyaluronan glycocalyx, regulating the efficiency of DC trafficking to lymph nodes. Our findings define a previously unrecognized role for CD44 in lymphatic trafficking and highlight the importance of the CD44:HA:LYVE-1 axis in its regulation.

scholarly journals Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses

2013 ◽  
Vol 210 (8) ◽  
pp. 1509-1528 ◽  
Author(s):  
Suvendu Das ◽  
Eliana Sarrou ◽  
Simona Podgrabinska ◽  
Melanie Cassella ◽  
Sathish Kumar Mungamuri ◽  
...  
Keyword(s):  
Cell Migration ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Lymphatic Vessels ◽  
Cell Entry ◽  
Human Malignant Melanoma ◽  
Tumor Cell Migration ◽  
Mouse Tissues

Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively by the flow of lymph. We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node, which requires active tumor cell migration. In human and mouse tissues, CCL1 protein is detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. CCR8, the receptor for CCL1, is strongly expressed by human malignant melanoma. Tumor cell migration to lymphatic endothelial cells (LECs) in vitro is inhibited by blocking CCR8 or CCL1, and recombinant CCL1 promotes migration of CCR8+ tumor cells. The proinflammatory mediators TNF, IL-1β, and LPS increase CCL1 production by LECs and tumor cell migration to LECs. In a mouse model, blocking CCR8 with the soluble antagonist or knockdown with shRNA significantly decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1–CCR8 in metastasis and lymph node LECs as a critical checkpoint for the entry of metastases into the lymph nodes.

The Lymph Node Niche.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-51-SCI-51
Author(s):  
Thorsten R. Mempel
Keyword(s):  
Lymph Nodes ◽  
B Lymphocyte ◽  
Immune Cell ◽  
Conflicts Of Interest ◽  
Lymphatic Vessels ◽  
Potential Threat ◽  
Peripheral Tissues ◽  
Pathogen Invasion ◽  
Cognate Antigen

Abstract Abstract SCI-51 Lymph nodes provide specialized stromal environments that support the maintenance and homeostasis of T and B lymphocyte populations and are also staging grounds for lymphocyte effector responses against pathogens and transformed cells. They serve as immune information hotspots by collecting lymph fluid from peripheral tissues, especially our external and internal epithelial body surfaces, thus displaying a condensed representation of foreign and self-antigens at these sites in addition to integrating innate alarm signals that report tissue damage or pathogen invasion. Naïve B and T cells constantly traffic through these environments via the blood stream and efferent lymphatic vessels, which allows for efficient matching of their antigen receptor repertoires with the regional antigenic landscape. Depending on the absence or presence of signs of a potential threat to the organism, the result may be either tolerance or immunity towards the origin of these antigens. The architecture of lymph nodes is optimized to facilitate the presentation of lymph-borne antigen in various forms and to guide naïve lymphocytes in their search for 'their' cognate antigen in the form in which they are able to 'see' it. It also facilitates the cellular crosstalk with other immune cell populations that shape and regulate an ensuing adaptive response if cognate antigen is encountered in an immunogenic context. Our conception of how these various tasks are accomplished has recently been enriched through new methodological approaches that include the dynamic in situ or in vivo visualization of cellular and molecular processes using modern microscopy technology. We will review some recent insights into the function of lymph nodes derived from these studies. Disclosures No relevant conflicts of interest to declare.

Nitric Oxide Transport in Lymphatic Vessels

2011 ◽  
Author(s):  
John T. Wilson ◽  
Rebecca L. Dahlin ◽  
Olga Gasheva ◽  
David C. Zawieja ◽  
James E. Moore
Keyword(s):  
Lymph Nodes ◽  
Lymphatic System ◽  
Physiological Function ◽  
Lymphatic Vessels ◽  
Vital Role ◽  
The Body ◽  
Common Pathway ◽  
Regional Lymph Nodes ◽  
Insight Into

The lymphatic system plays a vital role in maintaining proper physiological function in the body. Its removal of proteins and other particulate matter from the tissue spaces is particularly important for the body’s prevention of extracellular edema [1]. After fluid is absorbed by the initial lymphatics, it is transported to lymph nodes where filtration occurs. In addition, the lymphatic system serves as a common pathway of initial metastases to regional lymph nodes for certain types of cancers [2]. Thus, the characterization of mass transport in the lymphatic system could lead to unprecedented insight into the treatment of such pathologies.

scholarly journals Dense poly(ethylene glycol) coatings maximize nanoparticle transport across lymphatic endothelial cells

2020 ◽  
Author(s):  
Jacob McCright ◽  
Colin Skeen ◽  
Jenny Yarmovsky ◽  
Katharina Maisel
Keyword(s):  
Endothelial Cells ◽  
Ethylene Glycol ◽  
Lymph Nodes ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cells ◽  
Poly Ethylene Glycol ◽  
Nanoparticle Transport ◽  
Peripheral Tissues ◽  
Transport Efficiency ◽  
Poly Ethylene

AbstractLymphatic vessels have received considerable attention in recent years as delivery route for immune modulatory therapies to the lymph nodes. Lymph node targeting of immunotherapies and vaccines has been shown to significantly enhance their therapeutic efficacy. Lymphatics transport functions materials from peripheral tissues to the lymph nodes, including small 10 – 250 nm therapeutic nanoparticles. While size required to enter lymphatic vessels, surface chemistry is more poorly studied. Here, we probed the effects of surface poly(ethylene glycol) (PEG) density on nanoparticle transport across lymphatic endothelial cells (LECs). We differentially PEGylated model carboxylate-modified polystyrene nanoparticles to form either a brush or dense brush PEG conformation on the nanoparticle surfaces. Using an established in-vitro lymphatic transport model, we found that the addition of any PEG improved the transport of nanoparticles through lymphatic endothelial cells (2.5 - 2.6 ± 0.9% transport efficiency at 24 hours) compared to the unmodified PS-COOH nanoparticles (0.05 ± 0.05% transport efficiency at 24 hours). Additionally, we found that transcellular transport is maximized (4.2 ± 0.7% transport efficiency at 24 hours) when the PEG is in a dense brush conformation on nanoparticle surfaces, corresponding with a high grafting density (Rf/D = 4.9). These results suggest that PEG conformation has a crucial role in determining translocation of nanoparticles across LECs and into lymphatic vessels. Thus, we identified PEG density as a major design criteria for maximizing lymphatic targeting of therapeutic nanoparticle formulations that can be widely applied to enhance immunotherapeutic and vaccine outcomes in future studies.

scholarly journals Lymph-Derived Neutrophils Primarily Locate to the Subcapsular and Medullary Sinuses in Resting and Inflamed Lymph Nodes

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1486
Author(s):  
Jenny de Castro de Castro Pinho ◽  
Reinhold Förster
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Tissue Injury ◽  
Lymphatic Vessels ◽  
Functional Behavior ◽  
Subcapsular Sinus ◽  
Activated Neutrophils ◽  
Tissue Site

Neutrophils are the first immune cells to be recruited from the blood to the tissue site of an infection or inflammation. It has been suggested that neutrophils are capable of migrating from the infected tissue via lymphatic vessels to the draining lymph nodes. However, it remains elusive as to which areas within the lymph nodes can be reached by such reversely migrating cells. To address this question, we applied a model for adoptive neutrophil transfer into the afferent lymphatic vessel that drains towards the popliteal lymph node in mice. We showed that resting and in vitro-activated neutrophils did not enter the lymph node parenchyma but localized primarily in the subcapsular and medullary sinuses. Within the medulla, neutrophils show random migration and are able to sense laser-induced sterile tissue injury by massively swarming to the damaged tissue site. Co-injected dendritic cells supported the entry of resting neutrophils into the lymph node parenchyma via the subcapsular sinus. In contrast, in vivo-activated adoptively transferred neutrophils were capable of migrating into the interfollicular areas of the lymph node. Collectively, the data presented here give further insights into the functional behavior of neutrophils within the lymph nodes.

scholarly journals miR-203 Regulates Nociceptive Sensitization after Incision by Controlling Phospholipase A2 Activating Protein Expression

2012 ◽  
Vol 117 (3) ◽  
pp. 626-638 ◽  
Author(s):  
Yuan Sun ◽  
Xiang-Qi Li ◽  
Peyman Sahbaie ◽  
Xiao-You Shi ◽  
Wen-Wu Li ◽  
...  
Keyword(s):  
Substance P ◽  
Phospholipase A2 ◽  
Mechanical Allodynia ◽  
Gene Knockout ◽  
Skin Inflammation ◽  
Local Effect ◽  
Intraplantar Injection ◽  
Gene Knockout Mice

Background After incision keratinocytes in the epidermis become activated to produce a range of pain-related mediators. microRNA 203 (miR-203) is known to be involved in keratinocyte growth, differentiation, and skin inflammation. We hypothesized that one or more of these mediators might be under the control of miR-203. Methods The expression of miR-203 and its target gene, phospholipase A2 activating protein (PLAA), were examined after hind paw incision in mice. We investigated the local effect of intraplantar PLAA peptide injection in normal mice and the effects of a selective secretory phospholipase A2 inhibitor (HK064) on PLAA or incision-induced mechanical allodynia. Last, we investigated the role of substance P signaling in regulating miR-203 and PLAA expression in vitro and in vivo. Results Levels of miR-203 were strongly down-regulated in keratinocytes after incision. Informatics-based approaches identified PLAA as a likely candidate for regulation by miR-203. PLAA caused mechanical allodynia and conditioned place aversion but not thermal sensitization. HK064 reduced mechanical allodynia after incision and after intraplantar injection of PLAA. Using preprotachykinin gene knockout mice or with neurokinin-1 selective antagonist LY303870 treatment, we observed that substance P-mediated signaling was also required for miR-203 and PLAA regulation after incision. Finally, using the rat epidermal keratinocyte cell line, we observed that a miR-203 mimic molecule could block the substance P-induced increase in PLAA expression observed under control conditions. Conclusions miR-203 may regulate expression of the novel nociceptive mediator PLAA after incision. Furthermore, the regulation of miR-203 and PLAA levels is reliant upon intact substance P signaling.

scholarly journals Differential T Cell Function and Fate in Lymph Node and Nonlymphoid Tissues

2002 ◽  
Vol 195 (3) ◽  
pp. 317-326 ◽  
Author(s):  
Nicola L. Harris ◽  
Victoria Watt ◽  
Franca Ronchese ◽  
Graham Le Gros
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Nodes ◽  
Cell Function ◽  
Activated T Cells ◽  
Peripheral Tissues ◽  
Cell Immunity ◽  
Effector Cytokines

The functions and fate of antigen-experienced T cells isolated from lymph node or nonlymphoid tissues were analyzed in a system involving adoptive transfer of in vitro–activated T cells into mice. Activated T cells present in the lymph nodes could be stimulated by antigen to divide, produce effector cytokines, and migrate to peripheral tissues. By contrast, activated T cells that had migrated into nonlymphoid tissues (lung and airway) produced substantial effector cytokines upon antigen challenge, but were completely unable to divide or migrate back to the lymph nodes. Therefore, activated T cells can undergo clonal expansion in the lymph node, but are recruited and retained as nondividing cells in nonlymphoid tissues. These distinct regulatory events in lymph node and nonlymphoid tissues reveal simple key mechanisms for both inducing and limiting T cell immunity.

scholarly journals CD49b defines functionally mature Treg cells that survey skin and vascular tissues

2018 ◽  
Vol 215 (11) ◽  
pp. 2796-2814 ◽  
Author(s):  
Xiying Fan ◽  
Bruno Moltedo ◽  
Alejandra Mendoza ◽  
Alexey N. Davydov ◽  
Mehlika B. Faire ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Cell Subset ◽  
Treg Cells ◽  
Lymphoid Organs ◽  
Developmental Trajectory ◽  
Peripheral Tissues ◽  
Secondary Lymphoid Organs ◽  
Draining Lymph Nodes

Regulatory T (Treg) cells prevent autoimmunity by limiting immune responses and inflammation in the secondary lymphoid organs and nonlymphoid tissues. While unique subsets of Treg cells have been described in some nonlymphoid tissues, their relationship to Treg cells in secondary lymphoid organs and circulation remains unclear. Furthermore, it is possible that Treg cells from similar tissue types share largely similar properties. We have identified a short-lived effector Treg cell subset that expresses the α2 integrin, CD49b, and exhibits a unique tissue distribution, being abundant in peripheral blood, vasculature, skin, and skin-draining lymph nodes, but uncommon in the intestines and in viscera-draining lymph nodes. CD49b+ Treg cells, which display superior functionality revealed by in vitro and in vivo assays, appear to develop after multiple rounds of cell division and TCR-dependent activation. Accordingly, single-cell RNA-seq analysis placed these cells at the apex of the Treg developmental trajectory. These results shed light on the identity and development of a functionally potent subset of mature effector Treg cells that recirculate through and survey peripheral tissues.

A cell-surface molecule selectively expressed on murine natural interferon–producing cells that blocks secretion of interferon-alpha

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4201-4206 ◽  
Author(s):  
Amanda Blasius ◽  
William Vermi ◽  
Anne Krug ◽  
Fabio Facchetti ◽  
Marina Cella ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Interleukin 12 ◽  
Surface Molecule ◽  
Adaptive Responses ◽  
Cell Surface Molecule ◽  
Peripheral Tissues ◽  
Inflammatory Conditions ◽  
Inflammatory Stimuli

Abstract Natural interferon (IFN)-producing cells (IPCs) recognize certain viruses and DNA containing deoxycytidylate-phosphatedeoxyguanylate (CpG) motifs through the toll-like receptor (TLR) 9, resulting in secretion of IFN-α, interleukin 12 (IL-12), and proinflammatory chemokines. Human IPCs are found mainly in inflamed lymph nodes, where they are presumably recruited from the blood to activate both innate and adaptive responses to microbial infections. Demonstrating IPC recruitment and function in murine infection models has been difficult because multiple antibodies are required to distinguish IPCs from other immune cells and very few IPCs can be recovered from lymph nodes. Here we describe a monoclonal antibody (mAb) that exclusively detects murine IPCs in all lymphoid organs under both normal and inflammatory conditions. Using this antibody, we demonstrate that IPCs are normally present in the T-cell zone of lymph nodes and spleen and that inoculation of peripheral tissues with inflammatory stimuli triggers recruitment of IPC into sentinel lymph nodes, whether the stimuli are able to directly stimulate IPCs through TLR or not. Remarkably, we show that incubation of IPCs with the antibody in vitro or administration of the antibody in vivo dramatically reduce secretion of IFN-α in response to CpG DNA without causing IPC depletion. Thus, the antibody identifies an IPC-specific surface molecule that, when engaged, inhibits IFN-α secretion. (Blood. 2004;103:4201-4206)

Disrupted homeostasis of Langerhans cells and interdigitating dendritic cells in monkeys with AIDS

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2859-2868 ◽  
Author(s):  
Michael I. Zimmer ◽  
Adriana T. Larregina ◽  
Cielo M. Castillo ◽  
Saverio Capuano ◽  
Louis D. Falo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Langerhans Cells ◽  
Receptor Expression ◽  
Peripheral Tissues ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Draining Lymph Nodes

Abstract Langerhans cells (LCs) are immature dendritic cells (DCs) that capture antigen in peripheral tissues and migrate to draining lymph nodes, where they reside in the paracortex as interdigitating dendritic cells (IDCs). We studied the effects of simian immunodeficiency virus (SIV) on LCs and IDCs during different stages of infection in monkeys. LCs isolated from monkeys with acute SIV infection or acquired immunodeficiency syndrome (AIDS) underwent normal maturation in vitro, including a switch in chemokine receptor expression from CCR5 to CXCR4 and CCR7. LCs migrated normally from skin in response to contact sensitization in monkeys with acute SIV infection. In contrast, LC migration from skin was markedly impaired during AIDS, associated with a reduction in antigen-bearing DCs in draining lymph nodes. Lymph node IDCs were increased in proportion during acute SIV infection and had an activated phenotype, whereas during AIDS IDCs had significantly lower expression of CD40 and the activation marker CD83. IDCs from monkeys with AIDS were refractory to stimulation with CD40L, demonstrating a functional consequence of decreased CD40 expression. SIV-infected DCs were not identified in lymph nodes or skin of monkeys with AIDS, suggesting an indirect effect of infection on DC populations in vivo. These data indicate that DCs are mobilized to lymph nodes during acute SIV infection, but that during AIDS this process is suppressed, with LC migration and IDC activation being impaired. We conclude that disruption of DC homeostasis may play a role in immunopathology induced by human immunodeficiency virus and suggest that therapeutic strategies targeting DCs may have limited efficacy during AIDS.

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