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16 pages, 3528 KiB

Open AccessArticle

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

by Jenny de Castro Pinho and Reinhold Förster

Cells 2021, 10(6), 1486; https://doi.org/10.3390/cells10061486 - 12 Jun 2021

Cited by 12 | Viewed by 4097

Abstract

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. [...] Read more.

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. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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19 pages, 3885 KiB

Open AccessFeature PaperArticle

Single-Cell Transcriptional Heterogeneity of Lymphatic Endothelial Cells in Normal and Inflamed Murine Lymph Nodes

by Eliane Sibler, Yuliang He, Luca Ducoli, Nadja Keller, Noriki Fujimoto, Lothar C. Dieterich and Michael Detmar

Cells 2021, 10(6), 1371; https://doi.org/10.3390/cells10061371 - 2 Jun 2021

Cited by 18 | Viewed by 5550

Abstract

The lymphatic system plays a crucial role in immunity and lymph nodes (LNs) undergo drastic remodeling during inflammation. Here, we used single-cell RNA sequencing to investigate transcriptional changes in lymphatic endothelial cells (LECs) in LNs draining naïve and inflamed skin. We found that [...] Read more.

The lymphatic system plays a crucial role in immunity and lymph nodes (LNs) undergo drastic remodeling during inflammation. Here, we used single-cell RNA sequencing to investigate transcriptional changes in lymphatic endothelial cells (LECs) in LNs draining naïve and inflamed skin. We found that subsets of LECs lining the different LN sinuses responded individually to skin inflammation, suggesting that they exert distinct functions under pathological conditions. Among the genes dysregulated during inflammation, we confirmed an up-regulation of CD200 in the LECs lining the subcapsular sinus floor with a possible function in immune regulation. Furthermore, by in silico analysis, we predicted numerous possible interactions of LECs with diverse immune cells in the LNs and found similarities in the transcriptional changes of LN LECs in different skin inflammation settings. In summary, we provide an in-depth analysis of the transcriptional landscape of LN LECs in the naïve state and in skin inflammation. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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Review

Jump to: Research

13 pages, 4940 KiB

Open AccessReview

Pathogenic Exploitation of Lymphatic Vessels

by Alexandra I. Magold and Melody A. Swartz

Cells 2022, 11(6), 979; https://doi.org/10.3390/cells11060979 - 12 Mar 2022

Cited by 8 | Viewed by 4681

Abstract

Lymphatic vessels provide a critical line of communication between peripheral tissues and their draining lymph nodes, which is necessary for robust immune responses against infectious agents. At the same time, lymphatics help shape the nature and kinetics of immune responses to ensure resolution, [...] Read more.

Lymphatic vessels provide a critical line of communication between peripheral tissues and their draining lymph nodes, which is necessary for robust immune responses against infectious agents. At the same time, lymphatics help shape the nature and kinetics of immune responses to ensure resolution, limit tissue damage, and prevent autoimmune responses. A variety of pathogens have developed strategies to exploit these functions, from multicellular organisms like nematodes to bacteria, viruses, and prions. While lymphatic vessels serve as transport routes for the dissemination of many pathogens, their hypoxic and immune-suppressive environments can provide survival niches for others. Lymphatics can be exploited as perineural niches, for inter-organ distribution among highly motile carrier cells, as effective replicative niches, and as alternative routes in response to therapy. Recent studies have broadened our understanding of lymphatic involvement in pathogenic spread to include a wider range of pathogens, as well as new mechanisms of exploitation, which we summarize here. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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29 pages, 2426 KiB

Open AccessReview

Bacterial Lymphatic Metastasis in Infection and Immunity

by Matthew K. Siggins and Shiranee Sriskandan

Cells 2022, 11(1), 33; https://doi.org/10.3390/cells11010033 - 23 Dec 2021

Cited by 15 | Viewed by 5873

Abstract

Lymphatic vessels permeate tissues around the body, returning fluid from interstitial spaces back to the blood after passage through the lymph nodes, which are important sites for adaptive responses to all types of pathogens. Involvement of the lymphatics in the pathogenesis of bacterial [...] Read more.

Lymphatic vessels permeate tissues around the body, returning fluid from interstitial spaces back to the blood after passage through the lymph nodes, which are important sites for adaptive responses to all types of pathogens. Involvement of the lymphatics in the pathogenesis of bacterial infections is not well studied. Despite offering an obvious conduit for pathogen spread, the lymphatic system has long been regarded to bar the onward progression of most bacteria. There is little direct data on live virulent bacteria, instead understanding is largely inferred from studies investigating immune responses to viruses or antigens in lymph nodes. Recently, we have demonstrated that extracellular bacterial lymphatic metastasis of virulent strains of Streptococcus pyogenes drives systemic infection. Accordingly, it is timely to reconsider the role of lymph nodes as absolute barriers to bacterial dissemination in the lymphatics. Here, we summarise the routes and mechanisms by which an increasing variety of bacteria are acknowledged to transit through the lymphatic system, including those that do not necessarily require internalisation by host cells. We discuss the anatomy of the lymphatics and other factors that influence bacterial dissemination, as well as the consequences of underappreciated bacterial lymphatic metastasis on disease and immunity. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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30 pages, 2780 KiB

Open AccessReview

The Critical Importance of Spatial and Temporal Scales in Designing and Interpreting Immune Cell Migration Assays

by Jennifer Frattolin, Daniel J. Watson, Willy V. Bonneuil, Matthew J. Russell, Francesca Fasanella Masci, Mikaila Bandara, Bindi S. Brook, Robert J. B. Nibbs and James E. Moore, Jr.

Cells 2021, 10(12), 3439; https://doi.org/10.3390/cells10123439 - 7 Dec 2021

Cited by 4 | Viewed by 4175

Abstract

Intravital microscopy and other direct-imaging techniques have allowed for a characterisation of leukocyte migration that has revolutionised the field of immunology, resulting in an unprecedented understanding of the mechanisms of immune response and adaptive immunity. However, there is an assumption within the field [...] Read more.

Intravital microscopy and other direct-imaging techniques have allowed for a characterisation of leukocyte migration that has revolutionised the field of immunology, resulting in an unprecedented understanding of the mechanisms of immune response and adaptive immunity. However, there is an assumption within the field that modern imaging techniques permit imaging parameters where the resulting cell track accurately captures a cell’s motion. This notion is almost entirely untested, and the relationship between what could be observed at a given scale and the underlying cell behaviour is undefined. Insufficient spatial and temporal resolutions within migration assays can result in misrepresentation of important physiologic processes or cause subtle changes in critical cell behaviour to be missed. In this review, we contextualise how scale can affect the perceived migratory behaviour of cells, summarise the limited approaches to mitigate this effect, and establish the need for a widely implemented framework to account for scale and correct observations of cell motion. We then extend the concept of scale to new approaches that seek to bridge the current “black box” between single-cell behaviour and systemic response. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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11 pages, 775 KiB

Open AccessReview

Meningeal Lymphatics: An Immune Gateway for the Central Nervous System

by Gabriel A. Tavares and Antoine Louveau

Cells 2021, 10(12), 3385; https://doi.org/10.3390/cells10123385 - 1 Dec 2021

Cited by 26 | Viewed by 4819

Abstract

The recent (re)discovery of the meningeal lymphatic system has opened new theories as to how immune cells traffic and interact with the central nervous system (CNS). While evidence is accumulating on the contribution of the meningeal lymphatic system in both homeostatic and disease [...] Read more.

The recent (re)discovery of the meningeal lymphatic system has opened new theories as to how immune cells traffic and interact with the central nervous system (CNS). While evidence is accumulating on the contribution of the meningeal lymphatic system in both homeostatic and disease conditions, a lot remains unknown about the mechanisms that allow for interaction between the meningeal lymphatic system and immune cells. In this review, we synthesize the knowledge about the lymphatic immune interaction in the CNS and highlight the important questions that remain to be answered. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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22 pages, 944 KiB

Open AccessReview

Lymphatic Clearance of Immune Cells in Cardiovascular Disease

by Christophe Ravaud, Nikita Ved, David G. Jackson, Joaquim Miguel Vieira and Paul R. Riley

Cells 2021, 10(10), 2594; https://doi.org/10.3390/cells10102594 - 29 Sep 2021

Cited by 9 | Viewed by 4731

Abstract

Recent advances in our understanding of the lymphatic system, its function, development, and role in pathophysiology have changed our views on its importance. Historically thought to be solely involved in the transport of tissue fluid, lipids, and immune cells, the lymphatic system displays [...] Read more.

Recent advances in our understanding of the lymphatic system, its function, development, and role in pathophysiology have changed our views on its importance. Historically thought to be solely involved in the transport of tissue fluid, lipids, and immune cells, the lymphatic system displays great heterogeneity and plasticity and is actively involved in immune cell regulation. Interference in any of these processes can be deleterious, both at the developmental and adult level. Preclinical studies into the cardiac lymphatic system have shown that invoking lymphangiogenesis and enhancing immune cell trafficking in ischaemic hearts can reduce myocardial oedema, reduce inflammation, and improve cardiac outcome. Understanding how immune cells and the lymphatic endothelium interact is also vital to understanding how the lymphatic vascular network can be manipulated to improve immune cell clearance. In this Review, we examine the different types of immune cells involved in fibrotic repair following myocardial infarction. We also discuss the development and function of the cardiac lymphatic vasculature and how some immune cells interact with the lymphatic endothelium in the heart. Finally, we establish how promoting lymphangiogenesis is now a prime therapeutic target for reducing immune cell persistence, inflammation, and oedema to restore heart function in ischaemic heart disease. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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16 pages, 1911 KiB

Open AccessReview

Neutrophil Interactions with the Lymphatic System

by Arnolda Jakovija and Tatyana Chtanova

Cells 2021, 10(8), 2106; https://doi.org/10.3390/cells10082106 - 17 Aug 2021

Cited by 10 | Viewed by 6960

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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24 pages, 3160 KiB

Open AccessFeature PaperReview

Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System

by Louise A. Johnson and David G. Jackson

Cells 2021, 10(8), 2061; https://doi.org/10.3390/cells10082061 - 12 Aug 2021

Cited by 29 | Viewed by 4875

Abstract

Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions [...] Read more.

Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothelium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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23 pages, 5944 KiB

Open AccessReview

Lymphatic Trafficking in the Eye: Modulation of Lymphatic Trafficking to Promote Corneal Transplant Survival

by Yanhong Hou, Felix Bock, Deniz Hos and Claus Cursiefen

Cells 2021, 10(7), 1661; https://doi.org/10.3390/cells10071661 - 2 Jul 2021

Cited by 18 | Viewed by 3376

Abstract

(Lymph)angiogenesis into the cornea prior to and after corneal transplantation is a critical risk factor for allograft rejection. Lymphatic vessels even more than blood vessels seem important in mediating immune responses, as they facilitate allograft sensitization in the draining lymph nodes. Thus, the [...] Read more.

(Lymph)angiogenesis into the cornea prior to and after corneal transplantation is a critical risk factor for allograft rejection. Lymphatic vessels even more than blood vessels seem important in mediating immune responses, as they facilitate allograft sensitization in the draining lymph nodes. Thus, the concept of modulating lymphatic trafficking to promote corneal graft survival seems promising. A variety of approaches has been developed to inhibit progressive lymphangiogenesis in experimental settings. Recently, additionally to pharmacological approaches, clinically available techniques such as UVA-based corneal collagen crosslinking and fine needle diathermy were reported to be effective in regressing lymphatic vessels and to experimentally promote graft survival. Clinical pilot studies also suggest the efficacy of blocking antigen presenting cell trafficking to regional lymph nodes by regressing corneal lymphatic vessels to enhance allograft survival in high-risk eyes. In this article, we will give an overview of current strategies to modulate lymphatic trafficking with a special focus on recently reported strategies, which may be easy to translate into clinical practice. This novel concept of temporary, pretransplant regression of lymphatic vessels at the site of transplantation to promote subsequent corneal transplant survival (“lymphangioregressive preconditioning”) may also be applicable to other transplantation sites later. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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18 pages, 1117 KiB

Open AccessReview

Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis

by Kim Pin Yeo, Hwee Ying Lim and Veronique Angeli

Cells 2021, 10(6), 1344; https://doi.org/10.3390/cells10061344 - 29 May 2021

Cited by 8 | Viewed by 4768

Abstract

In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution [...] Read more.

In recent years, lymphatic vessels have received increasing attention and our understanding of their development and functional roles in health and diseases has greatly improved. It has become clear that lymphatic vessels are critically involved in acute and chronic inflammation and its resolution by supporting the transport of immune cells, fluid, and macromolecules. As we will discuss in this review, the involvement of lymphatic vessels has been uncovered in atherosclerosis, a chronic inflammatory disease of medium- and large-sized arteries causing deadly cardiovascular complications worldwide. The progression of atherosclerosis is associated with morphological and functional alterations in lymphatic vessels draining the diseased artery. These defects in the lymphatic vasculature impact the inflammatory response in atherosclerosis by affecting immune cell trafficking, lymphoid neogenesis, and clearance of macromolecules in the arterial wall. Based on these new findings, we propose that targeting lymphatic function could be considered in conjunction with existing drugs as a treatment option for atherosclerosis. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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25 pages, 912 KiB

Open AccessReview

Structure and Immune Function of Afferent Lymphatics and Their Mechanistic Contribution to Dendritic Cell and T Cell Trafficking

by Jorge Arasa, Victor Collado-Diaz and Cornelia Halin

Cells 2021, 10(5), 1269; https://doi.org/10.3390/cells10051269 - 20 May 2021

Cited by 27 | Viewed by 5856

Abstract

Afferent lymphatic vessels (LVs) mediate the transport of antigen and leukocytes to draining lymph nodes (dLNs), thereby serving as immunologic communication highways between peripheral tissues and LNs. The main cell types migrating via this route are antigen-presenting dendritic cells (DCs) and antigen-experienced T [...] Read more.

Afferent lymphatic vessels (LVs) mediate the transport of antigen and leukocytes to draining lymph nodes (dLNs), thereby serving as immunologic communication highways between peripheral tissues and LNs. The main cell types migrating via this route are antigen-presenting dendritic cells (DCs) and antigen-experienced T cells. While DC migration is important for maintenance of tolerance and for induction of protective immunity, T cell migration through afferent LVs contributes to immune surveillance. In recent years, great progress has been made in elucidating the mechanisms of lymphatic migration. Specifically, time-lapse imaging has revealed that, upon entry into capillaries, both DCs and T cells are not simply flushed away with the lymph flow, but actively crawl and patrol and even interact with each other in this compartment. Detachment and passive transport to the dLN only takes place once the cells have reached the downstream, contracting collecting vessel segments. In this review, we describe how the anatomy of the lymphatic network supports leukocyte trafficking and provide updated knowledge regarding the cellular and molecular mechanisms responsible for lymphatic migration of DCs and T cells. In addition, we discuss the relevance of DC and T cell migration through afferent LVs and its presumed implications on immunity. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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17 pages, 2902 KiB

Open AccessReview

LTβR Signaling Controls Lymphatic Migration of Immune Cells

by Wenji Piao, Vivek Kasinath, Vikas Saxena, Ram Lakhan, Jegan Iyyathurai and Jonathan S. Bromberg

Cells 2021, 10(4), 747; https://doi.org/10.3390/cells10040747 - 29 Mar 2021

Cited by 13 | Viewed by 7486

Abstract

The pleiotropic functions of lymphotoxin (LT)β receptor (LTβR) signaling are linked to the control of secondary lymphoid organ development and structural maintenance, inflammatory or autoimmune disorders, and carcinogenesis. Recently, LTβR signaling in endothelial cells has been revealed to regulate immune cell migration. Signaling [...] Read more.

The pleiotropic functions of lymphotoxin (LT)β receptor (LTβR) signaling are linked to the control of secondary lymphoid organ development and structural maintenance, inflammatory or autoimmune disorders, and carcinogenesis. Recently, LTβR signaling in endothelial cells has been revealed to regulate immune cell migration. Signaling through LTβR is comprised of both the canonical and non-canonical-nuclear factor κB (NF-κB) pathways, which induce chemokines, cytokines, and cell adhesion molecules. Here, we focus on the novel functions of LTβR signaling in lymphatic endothelial cells for migration of regulatory T cells (Tregs), and specific targeting of LTβR signaling for potential therapeutics in transplantation and cancer patient survival. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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23 pages, 1216 KiB

Open AccessReview

Progression of Metastasis through Lymphatic System

by Hengbo Zhou, Pin-ji Lei and Timothy P. Padera

Cells 2021, 10(3), 627; https://doi.org/10.3390/cells10030627 - 12 Mar 2021

Cited by 59 | Viewed by 9813

Abstract

Lymph nodes are the most common sites of metastasis in cancer patients. Nodal disease status provides great prognostic power, but how lymph node metastases should be treated is under debate. Thus, it is important to understand the mechanisms by which lymph node metastases [...] Read more.

Lymph nodes are the most common sites of metastasis in cancer patients. Nodal disease status provides great prognostic power, but how lymph node metastases should be treated is under debate. Thus, it is important to understand the mechanisms by which lymph node metastases progress and how they can be targeted to provide therapeutic benefits. In this review, we focus on delineating the process of cancer cell migration to and through lymphatic vessels, survival in draining lymph nodes and further spread to other distant organs. In addition, emerging molecular targets and potential strategies to inhibit lymph node metastasis are discussed. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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