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

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2605-2613 ◽  
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.

scholarly journals Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-Like Receptor 4

2020 ◽  
Vol 7 ◽  
Author(s):  
Zheng Xiao ◽  
Bin Kong ◽  
Hongjie Yang ◽  
Chang Dai ◽  
Jin Fang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cardiac Hypertrophy ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
New Technologies ◽  
Immune Cell ◽  
Current Knowledge ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling

Toll-like receptor 4 (TLR4), a key pattern recognition receptor, initiates the innate immune response and leads to chronic and acute inflammation. In the past decades, accumulating evidence has implicated TLR4-mediated inflammatory response in regulation of myocardium hypertrophic remodeling, indicating that regulation of the TLR4 signaling pathway may be an effective strategy for managing cardiac hypertrophy's pathophysiology. Given TLR4's significance, it is imperative to review the molecular mechanisms and roles underlying TLR4 signaling in cardiac hypertrophy. Here, we comprehensively review the current knowledge of TLR4-mediated inflammatory response and its interaction ligands and co-receptors, as well as activation of various intracellular signaling. We also describe the associated roles in promoting immune cell infiltration and inflammatory mediator secretion, that ultimately cause cardiac hypertrophy. Finally, we provide examples of some of the most promising drugs and new technologies that have the potential to attenuate TLR4-mediated inflammatory response and prevent or reverse the ominous cardiac hypertrophy outcomes.

scholarly journals Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation

Blood ◽  
2016 ◽  
Vol 128 (9) ◽  
pp. 1169-1173 ◽  
Author(s):  
John D. Welsh ◽  
Mark L. Kahn ◽  
Daniel T. Sweet
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Lymph Flow ◽  
The Body ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Circulation ◽  
Vessel Maturation

Abstract Aside from the established role for platelets in regulating hemostasis and thrombosis, recent research has revealed a discrete role for platelets in the separation of the blood and lymphatic vascular systems. Platelets are activated by interaction with lymphatic endothelial cells at the lymphovenous junction, the site in the body where the lymphatic system drains into the blood vascular system, resulting in a platelet plug that, with the lymphovenous valve, prevents blood from entering the lymphatic circulation. This process, known as “lymphovenous hemostasis,” is mediated by activation of platelet CLEC-2 receptors by the transmembrane ligand podoplanin expressed by lymphatic endothelial cells. Lymphovenous hemostasis is required for normal lymph flow, and mice deficient in lymphovenous hemostasis exhibit lymphedema and sometimes chylothorax phenotypes indicative of lymphatic insufficiency. Unexpectedly, the loss of lymph flow in these mice causes defects in maturation of collecting lymphatic vessels and lymphatic valve formation, uncovering an important role for fluid flow in driving endothelial cell signaling during development of collecting lymphatics. This article summarizes the current understanding of lymphovenous hemostasis and its effect on lymphatic vessel maturation and synthesizes the outstanding questions in the field, with relationship to human disease.

scholarly journals LTβR Signaling Controls Lymphatic Migration of Immune Cells

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 747
Author(s):  
Wenji Piao ◽  
Vivek Kasinath ◽  
Vikas Saxena ◽  
Ram Lakhan ◽  
Jegan Iyyathurai ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune Cell ◽  
Nuclear Factor Κb ◽  
Lymphoid Organ ◽  
The Novel ◽  
Lymphatic Endothelial Cells ◽  
Immune Cell Migration ◽  
Β Receptor ◽  
Pleiotropic Functions ◽  
Potential Therapeutics

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.

scholarly journals Loss of Primary Cilia Protein IFT20 Dysregulates Lymphatic Vessel Patterning in Development and Inflammation

2021 ◽  
Vol 9 ◽  
Author(s):  
Delayna Paulson ◽  
Rebecca Harms ◽  
Cody Ward ◽  
Mackenzie Latterell ◽  
Gregory J. Pazour ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Primary Cilia ◽  
Fluid Shear Stress ◽  
Lymphatic Vessels ◽  
Intraflagellar Transport ◽  
Membrane Receptors ◽  
Lymphatic Endothelial Cells ◽  
Corneal Lymphangiogenesis

Microenvironmental signals produced during development or inflammation stimulate lymphatic endothelial cells to undergo lymphangiogenesis, in which they sprout, proliferate, and migrate to expand the vascular network. Many cell types detect changes in extracellular conditions via primary cilia, microtubule-based cellular protrusions that house specialized membrane receptors and signaling complexes. Primary cilia are critical for receipt of extracellular cues from both ligand-receptor pathways and physical forces such as fluid shear stress. Here, we report the presence of primary cilia on immortalized mouse and primary adult human dermal lymphatic endothelial cells in vitro and on both luminal and abluminal domains of mouse corneal, skin, and mesenteric lymphatic vessels in vivo. The purpose of this study was to determine the effects of disrupting primary cilia on lymphatic vessel patterning during development and inflammation. Intraflagellar transport protein 20 (IFT20) is part of the transport machinery required for ciliary assembly and function. To disrupt primary ciliary signaling, we generated global and lymphatic endothelium-specific IFT20 knockout mouse models and used immunofluorescence microscopy to quantify changes in lymphatic vessel patterning at E16.5 and in adult suture-mediated corneal lymphangiogenesis. Loss of IFT20 during development resulted in edema, increased and more variable lymphatic vessel caliber and branching, as well as red blood cell-filled lymphatics. We used a corneal suture model to determine ciliation status of lymphatic vessels during acute, recurrent, and tumor-associated inflammatory reactions and wound healing. Primary cilia were present on corneal lymphatics during all of the mechanistically distinct lymphatic patterning events of the model and assembled on lymphatic endothelial cells residing at the limbus, stalk, and vessel tip. Lymphatic-specific deletion of IFT20 cell-autonomously exacerbated acute corneal lymphangiogenesis resulting in increased lymphatic vessel density and branching. These data are the first functional studies of primary cilia on lymphatic endothelial cells and reveal a new dimension in regulation of lymphatic vascular biology.

scholarly journals Porphyromonasgingivalis Lipopolysaccharide Antagonizes Escherichiacoli Lipopolysaccharide at Toll-Like Receptor 4 in HumanEndothelialCells

2003 ◽  
Vol 71 (12) ◽  
pp. 6799-6807 ◽  
Author(s):  
Stephen R. Coats ◽  
Robert A. Reife ◽  
Brian W. Bainbridge ◽  
Thu-Thao T. Pham ◽  
Richard P. Darveau
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Adaptor Protein ◽  
Dominant Negative ◽  
Toll Like Receptor ◽  
Human Endothelial Cells ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
E Coli ◽  
Signaling Complex

ABSTRACT E. coli lipopolysaccharide (LPS) induces cytokine and adhesion molecule expression via the toll-like receptor 4 (TLR4) signaling complex in human endothelial cells. In the present study, we investigated the mechanism by which Porphyromonas gingivalis LPS antagonizes E. coli LPS-dependent activation of human endothelial cells. P. gingivalis LPS at 1 μg/ml inhibited both E. coli LPS (10 ng/ml) and Mycobacterium tuberculosis heat shock protein (HSP) 60.1 (10 μg/ml) stimulation of E-selectin mRNA expression in human umbilical vein endothelial cells (HUVEC) without inhibiting interleukin-1 beta (IL-1β) stimulation. P. gingivalis LPS (1μ g/ml) also blocked both E. coli LPS-dependent and M. tuberculosis HSP60.1-dependent but not IL-1β-dependent activation of NF-κB in human microvascular endothelial (HMEC-1) cells, consistent with antagonism occurring upstream from the TLR/IL-1 receptor adaptor protein, MyD88. Surprisingly, P. gingivalis LPS weakly but significantly activated NF-κB in HMEC-1 cells in the absence of E. coli LPS, and the P. gingivalis LPS-dependent agonism was blocked by transient expression of a dominant negative murine TLR4. Pretreatment of HUVECs with P. gingivalis LPS did not influence the ability of E. coli LPS to stimulate E-selectin mRNA expression. Taken together, these data provide the first evidence that P. gingivalis LPS-dependent antagonism of E. coli LPS in human endothelial cells likely involves the ability of P. gingivalis LPS to directly compete with E. coli LPS at the TLR4 signaling complex.

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

Blood ◽  
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.

scholarly journals Investigating lymphangiogenesis in vitro and in vivo using engineered human lymphatic vessel networks

2021 ◽  
Vol 118 (31) ◽  
pp. e2101931118
Author(s):  
Shira Landau ◽  
Abigail Newman ◽  
Shlomit Edri ◽  
Inbal Michael ◽  
Shahar Ben-Shaul ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Blood Vessels ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cells ◽  
Supporting Cells ◽  
Vessel Formation ◽  
Vessel Networks

The lymphatic system is involved in various biological processes, including fluid transport from the interstitium into the venous circulation, lipid absorption, and immune cell trafficking. Despite its critical role in homeostasis, lymphangiogenesis (lymphatic vessel formation) is less widely studied than its counterpart, angiogenesis (blood vessel formation). Although the incorporation of lymphatic vasculature in engineered tissues or organoids would enable more precise mimicry of native tissue, few studies have focused on creating engineered tissues containing lymphatic vessels. Here, we populated thick collagen sheets with human lymphatic endothelial cells, combined with supporting cells and blood endothelial cells, and examined lymphangiogenesis within the resulting constructs. Our model required just a few days to develop a functional lymphatic vessel network, in contrast to other reported models requiring several weeks. Coculture of lymphatic endothelial cells with the appropriate supporting cells and intact PDGFR-β signaling proved essential for the lymphangiogenesis process. Additionally, subjecting the constructs to cyclic stretch enabled the creation of complex muscle tissue aligned with the lymphatic and blood vessel networks, more precisely biomimicking native tissue. Interestingly, the response of developing lymphatic vessels to tensile forces was different from that of blood vessels; while blood vessels oriented perpendicularly to the stretch direction, lymphatic vessels mostly oriented in parallel to the stretch direction. Implantation of the engineered lymphatic constructs into a mouse abdominal wall muscle resulted in anastomosis between host and implant lymphatic vasculatures, demonstrating the engineered construct's potential functionality in vivo. Overall, this model provides a potential platform for investigating lymphangiogenesis and lymphatic disease mechanisms.

Tanshinone IIA attenuates elastase-induced AAA in rats via inhibition of MyD88-dependent TLR-4 signaling

VASA ◽  
2014 ◽  
Vol 43 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Tao Shang ◽  
Feng Ran ◽  
Qian Qiao ◽  
Zhao Liu ◽  
Chang-Jian Liu
Keyword(s):  
Nuclear Factor Κb ◽  
Tanshinone Iia ◽  
Myeloid Differentiation ◽  
Aortic Tissue ◽  
Toll Like Receptor ◽  
Sprague Dawley ◽  
Toll Like Receptor 4 ◽  
Tissue Samples ◽  
Myeloid Differentiation Factor ◽  
And Control

Background: The purpose of this study was to determine whether myeloid differentiation factor88-dependent Toll-Like Receptor-4 (TLR-4) signaling contributed to the inhibition of abdominal aortic aneurysm (AAA) by Tanshinone IIA (Tan IIA). Materials and methods: Male Sprague-Dawley rats (n = 12 / group) were randomly distributed into three groups: Tan IIA, control, and sham. The rats from Tan IIA and control groups under-went intra-aortic elastase perfusion to induce AAAs, and those in the sham group were perfused with saline. Only the Tan IIA group received Tan IIA (2 mg / rat / d). Aortic tissue samples were harvested at 24 d after perfusion and evaluated using reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry and immunofluorescence. Results: The over-expression of Toll-Like Receptor-4 (TLR-4), Myeloid Differentiation factor 88 (MyD88), Phosphorylated Nuclear Factor κB (pNF-κB) and Phosphorylated IκBα (pIκBα) induced by elastase perfusion were significantly decreased by Tan IIA treatment. Conclusions: Tan IIA attenuates elastase-induced AAA in rats possibly via the inhibition of MyD88-dependent TLR-4 signaling, which may be one potential explanation of why Tan IIA inhibits AAA development through multiple effects.

scholarly journals CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the Toll-like receptor 4/nuclear factor-κB pathway

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052098094
Author(s):  
Shuang Qin ◽  
Li Li ◽  
Jia Liu ◽  
Jinrui Zhang ◽  
Qing Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Unexplained Recurrent Spontaneous Abortion ◽  
Tlr4 Antagonist

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

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