Locally Triggered Release of the Chemokine CCL21 Promotes Dendritic Cell Transmigration across Lymphatic Endothelia

Vaahtomeri, Kari; Brown, Markus; Hauschild, Robert; Vries, Ingrid de; Leithner, Alexander; Mehling, Matthias; Kaufmann, Walter A.; Sixt, Michael

doi:10.1016/j.celrep.2017.04.027

Cited by 66 publications

(72 citation statements)

References 43 publications

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“…Ccr3 CCL21 secretion from LECs [273]; mediates intralymphatic crawling [274,275]; and allows DCs to enter the lymph node parenchyma from the subcapsular sinus [276]. Thus, in addition to directing central tolerance, CCR7 is essential for peripheral tolerance and the initiation of adaptive immune responses [262].…”

Section: Ccr2mentioning

confidence: 99%

A guide to chemokines and their receptors

2018

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The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein‐coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behavior, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many nonleukocytic cell types. Chemokines are profoundly affected by post‐translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical ‘atypical’ chemokine receptors that regulate chemokine localization and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarizes the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focusing particularly on their ability to direct leukocyte migration.

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Section: Ccr2mentioning

confidence: 99%

A guide to chemokines and their receptors

2018

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“…Murine atherosclerotic lesions were found to harbor "atypical, 588 lymphatic-like" capillaries that were VEGFR3+ but LYVE1-(Taher et al, 2016), which is 589 consistent with our observations of adventitial LEC heterogeneity. Considering the critical role of 590 lymphatic EC-derived CCL21 in regulating the trafficking of APCs(Vaahtomeri et al, 2017), and 591 perhaps other adaptive immune cells, there is an impetus to determine the extent to which advential 592 lymphatics are a viable target for atherosclerosis therapy. 593…”

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confidence: 99%

Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta

Engelbrecht

Levesque

et al. 2019

Preprint

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26Despite the medical importance of G protein-coupled receptors (GPCRs), in vivo cellular 27 heterogeneity of GPCR signaling and downstream transcriptional responses are not understood. 28We report the comprehensive characterization of transcriptomes (bulk and single-cell) and 29 chromatin domains regulated by sphingosine 1-phosphate receptor-1 (S1PR1) in adult mouse 30 aortic endothelial cells. First, S1PR1 regulates NFkB and nuclear glucocorticoid receptor 31 pathways to suppress inflammation-related mRNAs. Second, spatially distinct S1PR1 signaling in 32 the aorta is associated with heterogenous endothelial cell (EC) subtypes. For example, a 33 transcriptomically distinct arterial EC population at vascular branch points (aEC1) exhibits ligand-34 independent S1PR1/ß-arrestin coupling. In contrast, circulatory S1P-dependent S1PR1/ß-arrestin 35 coupling was observed in non-branch point aEC2 cells that exhibit an inflammatory signature. 36Moreover, an adventitial lymphatic EC (LEC) population shows suppression of lymphangiogenic 37 and inflammation-related transcripts in a S1P/S1PR1-dependent manner. These insights add 38 resolution to existing concepts of GPCR signaling and S1P biology. 39 40 41 et al., 2014). Adapted from the "Tango" system (Barnea et al., 2008), S1PR1-GFP signaling 65 (S1PR1-GS) mice convert ß-arrestin recruitment to the GPCR to H2B-GFP expression (Kono et 66 al., 2014). We previously used the S1PR1-GS mouse and showed that high levels of endothelial 67 GFP expression (i.e. S1PR1/ß-arrestin coupling) are prominent at the lesser curvature of the aortic 68 arch and the orifices of intercostal branch points (Galvani et al., 2015). In addition, inflammatory 69 stimuli (e.g. lipopolysaccharide) induced rapid coupling of S1PR1 to ß-arrestin and GFP 70 expression in endothelium in an S1P-dependent manner (Kono et al., 2014). These data suggest 71 that the S1PR1-GS mouse is a valid model to study GPCR activation in vascular ECs in vivo. 72To gain insights into the molecular mechanisms of S1PR1 regulation of endothelial 73 transcription and the heterogenous nature of S1PR1 signaling in vivo, we performed bulk 74 transcriptome and open chromatin profiling of GFP high and GFP low aortic ECs from S1PR1-GS 75 mice. We also performed transcriptome and open chromatin profiling of aortic ECs in which S1pr1 76 was genetically ablated (S1pr1-ECKO) (Galvani et al., 2015). In addition, we conducted single-77 cell (sc) RNA-seq of GFP low and GFP high aortic ECs. Our results show that S1PR1 suppresses the 78 expression of inflammation-related mRNAs by inhibiting the NFkB pathway. Second, the high 79 S1PR1 signaling ECs (GFP high cells) are more similar to S1pr1-ECKO ECs at the level of the 80 transcriptome. Third, scRNA-seq revealed eight distinct aorta-associated EC populations 81 including six arterial EC subtypes, adventitial lymphatic ECs, and venous ECs, the latter likely 82 from the vasa vasorum. S1PR1 signaling was highly heterogenous within these EC subtypes but 83 was most frequent in adventitial LECs an...

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“…In order to selectively target actin in DCs and leave T cells unperturbed, we pre-treated DCs with the drug mycalolide B (mycB). MycB causes complete and lasting actin depolymerization by severing F-actin filaments and irreversible sequestration of G-actin (Hori et al, 1993;Saito et al, 1994;Vaahtomeri et al, 2017). In contrast to other drugs like cytochalasin D that has been used in earlier studies (Al-Alwan and Rowden, 2001), mycB leads to covalent modification and therefore cannot be washed out.…”

Section: Resultsmentioning

confidence: 99%

Dendritic cell actin dynamics controls T cell priming efficiency at the immunological synapse

Leithner

Altenburger

Hauschild

et al. 2020

Preprint

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Dendritic cells (DCs) are crucial for the priming of naïve T cells and the initiation of adaptive immunity. Priming is initiated at a heterologous cell-cell contact, the immunological synapse (IS). While it is established that actin dynamics regulates signalling at the T cell side of the contact, little is known about the cytoskeletal contribution on the DC side. We show that that the DC cytoskeleton is decisive for the formation of a multifocal synaptic structure, which correlates with T cell priming efficiency. We demonstrate that DC actin appears in transient foci at the IS and that these foci are dynamized by the WAVE complex. Absence of WAVE in DCs leads to stabilized contacts with T cells, caused by an increase in ICAM1-integrin mediated cell-cell adhesions. This results in a lower number of activated and proliferating T cells.Our results reveal an important role of DC actin in the regulation of synaptic contacts with crucial relevance for full T cell expansion.

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Locally Triggered Release of the Chemokine CCL21 Promotes Dendritic Cell Transmigration across Lymphatic Endothelia

Cited by 66 publications

References 43 publications

A guide to chemokines and their receptors

A guide to chemokines and their receptors

Sphingosine 1-phosphate-regulated transcriptomes in heterogenous arterial and lymphatic endothelium of the aorta

Dendritic cell actin dynamics controls T cell priming efficiency at the immunological synapse

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