Engineered Model of the Intestine Suggests Active Transport of Lipid by Lymphatics

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53903 ◽

2011 ◽

Author(s):

M. F. Faulkner ◽

J. Brandon Dixon

Keyword(s):

Molecular Motors ◽

Immune Cell ◽

Active Role ◽

Dietary Lipid ◽

Lipid Transport ◽

Cell Trafficking ◽

Lymphatic Endothelial Cells ◽

Lipid Trafficking ◽

Cell Tissue ◽

Lymphatic Diseases

The lymphatic system has long been thought of as little more than a series of passive ducts as they serve to return fluid and proteins from interstitial spaces back to the blood, provide a route for immune cell trafficking, and transport dietary lipid from the intestine to the blood. Recent evidence has revealed that the lymphatics play an active role in lipid trafficking, and alterations in this function have been correlated with the presence of lymphatic diseases (Dixon, 2010). Here we describe the use of a two-cell, tissue engineered model to explore mechanisms of lipid transport across lymphatic endothelial cells (LEC). Previously this model was demonstrated to recapitulate essential features of the intestinal-lacteal interface with in the mammalian gut (Dixon et al., 2009). With our model we demonstrate, not only that lipid transport across the lymphatics is transcellular and ATP dependent, but also, this mechanism of transport utilizes the molecular motors dynein and kinesin.

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Engineering Tools for Studying the Interplay Between Mechanics and Biology in Lymphatic Lipid Transport

ASME 2010 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2010-19364 ◽

2010 ◽

Author(s):

J. Brandon Dixon

Keyword(s):

Immune Cell ◽

Mechanical Load ◽

Contractile Function ◽

Lymphatic Vessels ◽

Dietary Lipid ◽

The Body ◽

Lipid Transport ◽

Cell Trafficking

The lymphatic vasculature extends through most tissues of the body and plays an essential role in maintaining fluid balance, immune cell trafficking, and lipid transport. Nearly all dietary lipid is transported from the intestine to the circulation via the lymphatic system in the form of triglyceride-rich lipoproteins called chylomicrons. This process can be described through two different mechanisms: 1) entry of the chylomicron into the initial lymphatic vessels of the small intestine, known as lacteals, and 2) the transport of these chylomicrons through the larger collecting lymphatics by a complex and coordinated system of individual contracting vessel units (lymphangions) and valve leaflets. We describe here a set of in vitro and in vivo tools we have developed to study the mechanisms that modulate lipid transport under these two different paradigms and show how these tools are uncovering important biological features involved in these mechanisms. Lymphatic pump function is known to be sensitive to the mechanical load on the vessel as the contractility of isolated vessels has been shown to be both shear and stretch sensitive [1], yet whether these mechanisms are important in regulating contractile function in vivo remains uncertain.

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The role of lymphatics in intestinal inflammation

Inflammation and Regeneration ◽

10.1186/s41232-021-00175-6 ◽

2021 ◽

Vol 41 (1) ◽

Cited By ~ 1

Author(s):

Ryota Hokari ◽

Akira Tomioka

Keyword(s):

Immune Cell ◽

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Dietary Lipid ◽

Peripheral Tolerance ◽

Lipid Absorption ◽

Lymphoid Tissues ◽

Cell Trafficking ◽

Lymphocyte Migration ◽

And Function

AbstractThe lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn’s disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer’s disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.

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HIV Envelope Protein gp120 Stimulates Expression of Specific Chemokines in Lymphatic Endothelial Cells.

Blood ◽

10.1182/blood.v104.11.3102.3102 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3102-3102

Author(s):

Xuefeng Zhang ◽

Jian Feng Wang ◽

Jerome E. Groopman

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Cell ◽

Cell Trafficking ◽

Lymphatic Endothelial Cells ◽

Infected Cells ◽

Hiv Envelope ◽

Hiv 1

Abstract Lymphoid organs are the major anatomical home of HIV, where the virus replicates during both the acute and chronic phases of infections. In this regard, there are significantly more infected cells in lymph nodes (LNs) than in circulating blood, and these infected cells are a major reservoir of infectious HIV. Certain chemokines like CCL19 (MIP-3β) and CCL21 (SLC) play key roles in immune cell trafficking to LNs. They induce specific homing of naïve T cells and dendritic cells into the T cell zone of secondary lymphoid organs. There, the T cells become activated by the dendritic cells. A network of channels composed of lymphatic endothelium exists in LNs that provides a route for this dendritic cell and T cell movement. To date, how this lymphatic endothelium may contribute to the pathogenesis of HIV infection has not been studied. This prompted us to investigate whether HIV may alter immune cell trafficking via interaction with this lymphatic network. Lymphatic endothelial cells (LEC) were separated from primary dermal microvascular endothelial cells. The phenotype of LEC was confirmed by immunostaining with specific lymphatic markers including VEGFR-3, LYVE-1, and podoplanin. Since HIV envelope proteins are presented to endothelial cells in the microenvironment, we studied the effects of X4 gp120 on LEC. Using a pathway specific cDNA array, we detected enhanced expression of a restricted repertoire of chemokines in LEC upon HIV-1 gp120 stimulation. Gp120 upregulated expression of the chemokine genes GRO-α, GRO-γ, MIP-3β, and SDF-1α and β in LEC. These chemokines can act to enhance T cell and dendritic cell homing to LNs. Furthermore, we also detected GRO-α, SDF-1, and SLC proteins in culture supernatants of the gp120-treated LEC. We did not observe upregulation of the chemokines RANTES and MCP-1 upon gp120 stimulation. Since dendritic cells mediate the HIV infectivity of CD4+ T cells by presenting HIV particles, our study suggests that HIV-1 gp120-induced production of a restricted repertoire of chemokines in LEC may accelerate the trafficking of infected dendritic cells to LNs and foster HIV infection in this reservoir.

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Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages

Blood ◽

10.1182/blood-2008-07-166934 ◽

2009 ◽

Vol 113 (11) ◽

pp. 2605-2613 ◽

Cited By ~ 78

Author(s):

Shinae Kang ◽

Seung-Pyo Lee ◽

Kyung Eun Kim ◽

Hak-Zoo Kim ◽

Sylvie Mémet ◽

...

Keyword(s):

Endothelial Cells ◽

Lymphatic Vessel ◽

Immune Cell ◽

Lymphatic Vessels ◽

Nuclear Factor Κb ◽

Cell Trafficking ◽

Lymphatic Endothelial Cells ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Tlr4 Signaling

The lymphatic vessel is a major conduit for immune cell transport; however, little is known about how lymphatic vessels regulate immune cell trafficking and how lymphatic vessels themselves respond to inflammation. Toll-like receptor 4 (TLR4) plays a central role in lipopolysaccharide (LPS)–induced inflammation, but the role of TLR4 in lymphatic endothelial cells (LECs) is poorly understood. Here, we found that LECs express high amounts of TLR4 in the intracellular region, and that the TLR4 of LECs is the main mediator of nuclear factor–κB (NF-κB) activation by LPS. LPS-TLR4 signaling in LECs resulted in the production of various chemokines for chemotaxis of macrophage. In addition, TLR4 in LECs actively contributed to the recruitment of macrophages to the draining lymphatic vessel. Furthermore, the macrophages that infiltrated into the lymphatic vessel induced lymphangiogenesis by secreting lymphangiogenic growth factors. These phenomena were largely attenuated not only in the mice defective in TLR4 signaling but also in the chimeric mice defective in TLR4 signaling that were recipients for bone marrow transplantation from normal TLR4-signaling mice. In conclusion, TLR4 in LECs plays an essential role in LPS-induced inflammatory lymphangiogenesis by chemotactic recruitment of macrophages.

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Lymphangiogenesis: fuel, smoke, or extinguisher of inflammation’s fire?

Experimental Biology and Medicine ◽

10.1177/1535370217697385 ◽

2017 ◽

Vol 242 (8) ◽

pp. 884-895 ◽

Cited By ~ 18

Author(s):

Gabriella R Abouelkheir ◽

Bradley D Upchurch ◽

Joseph M Rutkowski

Keyword(s):

Immune Cell ◽

Cell Activity ◽

Lymphatic Vessels ◽

Active Role ◽

The Body ◽

Cell Trafficking ◽

Resolution Of Inflammation ◽

Immune Cell Trafficking ◽

Disease States ◽

Inflammatory Processes

Lymphangiogenesis is a recognized hallmark of inflammatory processes in tissues and organs as diverse as the skin, heart, bowel, and airways. In clinical and animal models wherein the signaling processes of lymphangiogenesis are manipulated, most studies demonstrate that an expanded lymphatic vasculature is necessary for the resolution of inflammation. The fundamental roles that lymphatics play in fluid clearance and immune cell trafficking from the periphery make these results seemingly obvious as a mechanism of alleviating locally inflamed environments: the lymphatics are simply providing a drain. Depending on the tissue site, lymphangiogenic mechanism, or induction timeframe, however, evidence shows that inflammation-associated lymphangiogenesis (IAL) may worsen the pathology. Recent studies have identified lymphatic endothelial cells themselves to be local regulators of immune cell activity and its consequential phenotypes – a more active role in inflammation regulation than previously thought. Indeed, results focusing on the immunocentric roles of peripheral lymphatic function have revealed that the basic drainage task of lymphatic vessels is a complex balance of locally processed and transported antigens as well as interstitial cytokine and immune cell signaling: an interplay that likely defines the function of IAL. This review will summarize the latest findings on how IAL impacts a series of disease states in various tissues in both preclinical models and clinical studies. This discussion will serve to highlight some emerging areas of lymphatic research in an attempt to answer the question relevant to an array of scientists and clinicians of whether IAL helps to fuel or extinguish inflammation. Impact statement Inflammatory progression is present in acute and chronic tissue pathologies throughout the body. Lymphatic vessels play physiological roles relevant to all medical fields as important regulators of fluid balance, immune cell trafficking, and immune identity. Lymphangiogenesis is often concurrent with inflammation and can potentially aide or worsen disease progression. How new lymphatic vessels impact inflammation and by which mechanism is an important consideration in current and future clinical therapies targeting inflammation and/or vasculogenesis. This review identifies, across a range of tissue-specific pathologies, the current understanding of inflammation-associated lymphangiogenesis in the progression or resolution of inflammation.

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The potassium channel KCNK2 is a regulator of immune cell trafficking and inflammatory responses in idiopathic inflammatory myopathies

10.1055/s-0039-1684986 ◽

2019 ◽

Author(s):

T Müntefering ◽

A Michels ◽

SG Meuth ◽

T Ruck

Keyword(s):

Potassium Channel ◽

Immune Cell ◽

Inflammatory Responses ◽

Idiopathic Inflammatory Myopathies ◽

Cell Trafficking ◽

Inflammatory Myopathies ◽

Immune Cell Trafficking

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New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

Current Medicinal Chemistry ◽

10.2174/0929867324666170830094922 ◽

2018 ◽

Vol 25 (36) ◽

pp. 4758-4784 ◽

Cited By ~ 8

Author(s):

Amy L. Wilson ◽

Magdalena Plebanski ◽

Andrew N. Stephens

Keyword(s):

Clinical Trials ◽

Cell Death ◽

Immune System ◽

Cancer Therapy ◽

Immune Cell ◽

Cytotoxic T Lymphocyte ◽

Tumour Microenvironment ◽

Immune Checkpoints ◽

Tumour Regression ◽

Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

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The Therapeutic Potential of Chemokines in the Treatment of Chemotherapy- Induced Peripheral Neuropathy

Current Drug Targets ◽

10.2174/1389450120666190906153652 ◽

2020 ◽

Vol 21 (3) ◽

pp. 288-301 ◽

Cited By ~ 5

Author(s):

Lin Zhou ◽

Luyao Ao ◽

Yunyi Yan ◽

Wanting Li ◽

Anqi Ye ◽

...

Keyword(s):

Nervous System ◽

Neuropathic Pain ◽

Immune System ◽

Peripheral Neuropathy ◽

Immune Cell ◽

Therapeutic Potential ◽

Chemotherapeutic Agents ◽

Cell Trafficking ◽

Mediated Communication ◽

Novel Therapeutic Strategies

Background: Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system. Objective: In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour. Conclusion: By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN.

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