P2Y receptor signaling regulates phenotype and IFN-α secretion of human plasmacytoid dendritic cells

Shin, Amanda; Toy, Tracey; Rothenfußer, Simon; Robson, Neil C.; Vorac, Julia; Dauer, Marc; Stuplich, Moritz; Endres, Stefan; Cebon, Jonathan; Maraskovsky, Eugene; Schnurr, Max

doi:10.1182/blood-2007-02-071910

Cited by 44 publications

(35 citation statements)

References 42 publications

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“…P2Y 14 receptor transcripts are expressed in several human tissues, including placenta, stomach, intestine, adipose, brain, lung, spleen, heart, and circulating leukocytes (3,(5)(6)(7). UDPsugar-promoted signaling has been reported in astrocytes and microglial cells (8,9), lung epithelial cells (10), bone marrow hematopoietic stem cells (11), and multiple types of peripheral immune cells, including neutrophils, lymphocytes, and dendritic cells (6,7,12,13). These observations suggest that UDPsugars, high energy donor substrates in biosynthetic reactions, potentially are released from cells in a regulated fashion to perform autocrine/paracrine signaling.…”

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confidence: 88%

“…P2Y receptors belong to the superfamily of G protein-coupled receptors. At least eight human P2Y receptor species have been identified, seven of which (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , and P2Y 13 ) are activated by adenine and/or uridine nucleoside di-and triphosphates (2). The P2Y 14 receptor was identified as the eighth member of the P2Y family (3,4).…”

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confidence: 99%

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Endoplasmic Reticulum/Golgi Nucleotide Sugar Transporters Contribute to the Cellular Release of UDP-sugar Signaling Molecules

Sesma

Esther

Kreda

et al. 2009

Journal of Biological Chemistry

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Extracellular UDP-sugars promote cellular responses by interacting with widely distributed P2Y 14 receptors, but the mechanisms by which these molecules are released from cells are poorly understood. Given the active role of UDP-sugars in glycosylation reactions within the secretory pathway, we hypothesized that UDP-sugar release includes an exocytotic component. This hypothesis was tested by assessing the contribution of endoplasmic reticulum (ER)/Golgi-resident UDPGlcNAc transporters to the cellular release of their cognate substrates. A sensitive and highly selective assay for UDP-GlcNAc mass was developed using purified AGX2, an isoenzyme of human UDP-GlcNAc pyrophosphorylase. Robust constitutive release of UDP-GlcNAc was observed in yeast as well as in well differentiated human airway epithelial cells. The human UDPGlcNAc transporter HFRC1 was overexpressed in human bronchial epithelial cells and was shown to localize in the Golgi and to enhance the surface expression of N-acetylglucosamine-rich glycans. HFRC1-overexpressing cells also displayed increased constitutive and hypotonic stress-stimulated release of UDPGlcNAc. Yeast mutants lacking Yea4 (the ER UDP-GlcNAc transporter endogenously expressed in Saccharomyces cerevisiae) showed reduced UDP-GlcNAc release. Yea4-deficient cells complemented with Yea4 showed UDP-GlcNAc release rates at levels similar to or higher than wild type cells. Our results illustrate that ER/Golgi lumen constitutes a significant source of extracellular UDP-sugars and therefore plays a critical role in nucleotide sugar-promoted cell signaling.Extracellular nucleotides perform important signaling functions via activation of broadly distributed P2X and P2Y purinergic receptors (1, 2). P2X receptors comprise seven species (P2X 1 -P2X 7 ) of ATP-gated ion channels. P2Y receptors belong to the superfamily of G protein-coupled receptors. At least eight human P2Y receptor species have been identified, seven of which (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , and P2Y 13 ) are activated by adenine and/or uridine nucleoside di-and triphos-

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confidence: 88%

mentioning

confidence: 99%

Endoplasmic Reticulum/Golgi Nucleotide Sugar Transporters Contribute to the Cellular Release of UDP-sugar Signaling Molecules

Sesma

Esther

Kreda

et al. 2009

Journal of Biological Chemistry

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“…One of such examples is the synergism between both families in the activation of dendritic cells, which is necessary for the efficient initiation of immune responses. In addition to Ag, the presence of P2 agonists coming from necrotic cells results in a synergistic activation and maturation of dendritic cells and, therefore, in a more efficient signaling in T cells, leading to a higher expression of proinflammatory mediators and adhesion molecules (3,49,50).…”

Section: Discussionmentioning

confidence: 99%

Selective Impairment of P2Y Signaling by Prostaglandin E2 in Macrophages: Implications for Ca2+-Dependent Responses

Través

Pimentel-Santillana

Carrasquero

et al. 2013

The Journal of Immunology

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Extracellular nucleotides have been recognized as important modulators of inflammation via their action on specific pyrimidine receptors (P2). This regulation coexists with the temporal framework of proinflammatory and proresolution mediators released by the cells involved in the inflammatory response, including macrophages. Under proinflammatory conditions, the expression of cyclooxygenase-2 leads to the release of large amounts of PGs, such as PGE2, that exert their effects through EP receptors and other intracellular targets. The effect of these PGs on P2 receptors expressed in murine and human macrophages was investigated. In thioglycollate-elicited and alternatively activated macrophages, PGE2 selectively impairs P2Y but not P2X7 Ca2+ mobilization. This effect is absent in LPS-activated cells and is specific for PGE2 because it cannot be reproduced by other PGs with cyclopentenone structure. The inhibition of P2Y responses by PGE2 involves the activation of nPKCs (PKCε) and PKD that can be abrogated by selective inhibitors or by expression of dominant-negative forms of PKD. The inhibition of P2Y signaling by PGE2 has an impact on the cell migration elicited by P2Y agonists in thioglycollate-elicited and alternatively activated macrophages, which provide new clues to understand the resolution phase of inflammation, when accumulation of PGE2, anti-inflammatory and proresolving mediators occurs.

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“…subject. Recent studies have shown that extracellular nucleotides, such as UDP, can modulate the function and IFN-a production of human pDCs through the P2Y6 receptor, which is mainly expressed on pDCs, not T cells (35,36). Thus, it is likely that the function of uGD-derived DCs is reversed by the P2Y6 ligand.…”

Section: Proportionmentioning

confidence: 99%

Impairment of Regulatory Capacity of CD4+CD25+ Regulatory T Cells Mediated by Dendritic Cell Polarization and Hyperthyroidism in Graves’ Disease

Mao

Shu

Xiao

et al. 2011

The Journal of Immunology

126

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Graves’ disease (GD) is one of the most common autoimmune diseases. The immune dysfunction in GD involves the generation of thyroid-stimulating hormone receptor (TSHR) autoantibodies that presumably arise consequent to interactions among dendritic cells (DCs), T cells, and regulatory T (Treg) cells. However, the immunological mechanisms of interactions between them that lead to the induction and regulation of this autoimmune disease are poorly defined. In this study, we investigated whether DCs are the main cause of the defective activity of Treg cells in GD patients. We found a significant decrease in the percentage of circulating CD4+CD25+FOXP3+ Treg cells in untreated GD patients (uGD), which was negatively correlated with the concentration of TSHR autoantibodies. uGD-derived DCs were polarized to increase the number of plasmacytoid DCs (pDCs) and conferred the ability to abrogate the suppressive function of Treg cells through inducing apoptosis of CD4+CD25+ Treg cells in an IFN-α–dependent manner, and elevated thyroid hormones further exacerbated the effect. The nucleotide UDP, which inhibits IFN-α secretion of pDCs through P2Y6 receptor signaling, restored the suppressive function of CD4+CD25+ Treg cells. Collectively, uGD-derived DCs through pDC polarization and elevated thyroid hormones act in concert to impair the regulatory capacity of Treg cells, facilitating the production of TSHR autoantibodies in the pathogenesis of GD.

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P2Y receptor signaling regulates phenotype and IFN-α secretion of human plasmacytoid dendritic cells

Abstract: Plasmacytoid dendritic cells (PDCs

Cited by 44 publications

References 42 publications

Endoplasmic Reticulum/Golgi Nucleotide Sugar Transporters Contribute to the Cellular Release of UDP-sugar Signaling Molecules

Endoplasmic Reticulum/Golgi Nucleotide Sugar Transporters Contribute to the Cellular Release of UDP-sugar Signaling Molecules

Selective Impairment of P2Y Signaling by Prostaglandin E2 in Macrophages: Implications for Ca2+-Dependent Responses

Impairment of Regulatory Capacity of CD4+CD25+ Regulatory T Cells Mediated by Dendritic Cell Polarization and Hyperthyroidism in Graves’ Disease

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