Open Journal Systems

Role of the P2Y6 receptor of UDP in the modulation of murine dendritic cell functions and Th1 polarisation of the immune response

Dorothée Cammarata, Abduelhakem Ben Addi, Eva D’Amico, Bernard Robaye

Article ID: 140
Vol 3, Issue 1, 2018, Article identifier:30-37

VIEWS - 691 (Abstract) 469 (PDF)


Numerous studies have demonstrated the role of uridine diphosphate (UDP) and its P2Y6 receptor in the inflammatory reaction and innate immunity. However, the importance of the P2Y6 receptor in the adaptive immune response remains unclear. In this study, we demonstrate that the P2Y6 receptor is functionally expressed in murine bone marrow dendritic cells (BMDC). UDP induced a Ca2+ transient in these cells that was decreased in P2Y6-deficient mice. UDP also increased the endocytosis of fluorescein isothiocyanate-dextran (FITC-dextran) and amplified the secretion of interleukin 12-p70 (IL-12p70) induced by CpG; these responses were abolished in P2Y6-deficient mice. In vivo experiments showed that the serum level of specific IgG2c after immunisation with ovalbumin was decreased in P2Y6-deficient mice, while the level of specific IgG1 was unchanged. These data suggest that the P2Y6-mediated effects of UDP on myeloid dendritic cells play a role in the in vivo Th1 skewing of the immune response.


adaptive immunity; dendritic cells; UDP; P2Y6 receptor

Full Text:


Included Database


Junger W G, 2011, Immune cell regulation by autocrine purinergic signaling. Nature Review Immunology, vol.11: 201–212.

Di Virgilio F, Boeynaems J M and Robson SC, 2009, Extracellular nucleotides as negative modulators of immunity. Current Opinion in Pharmacology, vol.9(4): 507–513.

Idzko M, Ferrari D and Eltzschig H K, 2014, Nucleotide signalling during inflammation. Nature, vol.509: 310–317.

Lazarowski E R, Boucher R C and Harden T K, 2003, Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Molecular Pharmacology, vol.64(4): 785–795.

Boeynaems J M, Communi D, Gonzalez N S, et al. 2005, Overview of the P2 receptors. Seminars in Thrombosis and Hemostasis, vol.31(2): 139–149.

Boeynaems J M, Communi D and Robaye B, 2012, Overview of the pharmacology and physiological roles of P2Y receptors. Wiley Interdisciplinary Reviews: Membrane Transport and Signalling, vol.1(5): 581–588.

Syed N I H and Kennedy C, 2011, Pharmacology of P2X receptors. Wiley Interdisciplinary Reviews: Membrane Transport and Signalling, vol.1(1): 16–30.

Ben Addi A, Cammarata D, Conley P B, et al. 2010, Role of the P2Y12 receptor in the modulation of murine dendritic cell function by ADP. Journal of Immunology, vol.185(10): 5900–5906.

Warny M, Aboudola S, Robson S C, et al. 2001, P2Y6 nucleotide receptor mediates monocyte interleukin-8 production in response to UDP or lipopolysaccharide. Journal of Biological Chemistry, vol.276: 26051–26056.

Bar I, Guns P J, Metallo J, et al. 2008, Knockout mice reveal a role for P2Y6 receptor in macrophages, endothelial cells, and vascular smooth muscle cells. Molecular Pharmacology, vol.74(3): 777–784.

Kukulski F, Ben Yebdri F, Lefebvre J, et al. 2007, Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo. Journal of Leukocyte Bi-ology, vol.81(5): 1269–1275.

Ben Yebdri F, Kukulski F, Tremblay A, et al. 2009, Con-comitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2-induced neutrophil migration by regulating IL-8 secretion. European Journal of Immunology, vol.39(10): 2885–2894.

Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, et al. 2007, UDP acting at P2Y6 receptors is a mediator of mi-croglial phagocytosis. Nature, vol.446: 1091–1095.

Inoue K., Koizumi S, Kataoka A, et al. 2009, P2Y6-evoked microglial phagocytosis. International Review of Neurobiology, vol.85: 159–163.

Grbic D M, Degagné É, Langlois C, et al. 2008, Intestinal inflammation increases the expression of the P2Y6 receptor on epithelial cells and the release of CXC chemokine ligand 8 by UDP. Journal of Immunology, vol.180(4): 2659–2668.

Grbic D M, Degagné É, Larrivée J F, et al. 2012, P2Y6 receptor contributes to neutrophil recruitment to inflamed intestinal mucosa by increasing CXC chemokine ligand 8 expression in an AP-1-dependent manner in epithelial cells. Inflammatory Bowel Diseases, vol.18(8): 1456–1469.

Hansen A, Alston L, Tulk S E, et al. 2013, The P2Y6 Receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction. PLoS ONE, vol.8(11): e81491.

Khine A A, Del Sorbo L, Vaschetto R, et al. 2006, Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway. Blood, vol.107: 2936–2942.

Vieira R P, Müller T, Grimm M, et al. 2011, P2Y6 receptor contributes to airway inflammation and remodeling in experimental allergic airway inflammation. American Journal of Respiratory and Critical Care Medicine, vol.184(2): 215–223.

Uratsuji H, Tada Y, Kawashima T, et al. 2012, P2Y6 receptor signaling pathway mediates inflammatory responses induced by monosodium urate crystals. Journal of Immunology, vol.188(1): 436–444.

Kim B, Jeong H, Kim J, et al. 2011, Uridine 5′-diphosphate induces chemokine expression in microglia and astrocytes through activation of the P2Y6 receptor. Journal of Immunology, vol.186(6): 3701–3709.

Riegel A K, Faigle M, Zug S, et al. 2011, Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation. Blood, vol.117: 2548–2555.

Marriott I, Inscho E W and Bost K L, 1999, Extracellular uridine nucleotides initiate cytokine production by murine dendritic cells. Cellular Immunology, vol.195(2): 147–156.

Idzko M, Panther E, Sorichter S, et al. 2004, Characterization of the biological activities of uridine diphosphate in human dendritic cells: influence on chemotaxis and CXCL8 release. Journal of Cellular Physiology, vol.201(2): 286–293.

Skelton L, Cooper M, Murphy M, et al. 2003, Human immature monocyte-derived dendritic cells express the G protein-coupled receptor GPR105 (KIAA0001, P2Y14) and increase intracellular calcium in response to its ago-nist, uridine diphosphoglucose. Journal of Immunology, vol.171(4): 1941–1949.

Fricks I P, Maddileti S, Carter R L, et al. 2008, UDP is a competitive antagonist at the human P2Y14 receptor. Journal of Pharmacology and Experimental Therapeutics, vol.325(2): 588–594.

Carter R L, Fricks I P, Barrett M O, et al. 2009, Quantification of Gi-mediated inhibition of adenylyl cyclase activity reveals that UDP is a potent agonist of the human P2Y14 receptor. Molecular Pharmacology, vol.76(6): 1341– 1348.

Shin A, Toy T, Rothenfusser S, et al. 2008, P2Y receptor signaling regulates phenotype and IFN-alpha secretion of human plasmacytoid dendritic cells. Blood, vol.111: 3062–3069.

Mao C, Wang S, Xiao Y, et al. 2011, Impairment of regulatory capacity of CD4+CD25+ regulatory T cells mediated by dendritic cell polarization and hyperthyroidism in Graves’ disease. Journal of Immunology, vol.186(8): 4734–4743.

Somers G R, Hammet F M, Trute L, et al. 1998, Expression of the P2Y6 purinergic receptor in human T cells infiltrating inflammatory bowel disease. Laboratory Investigation, vol.78(11): 1375–1383.

Giannattasio G, Ohta S, Boyce J R, et al. 2011, The purinergic G protein-coupled receptor 6 inhibits effector T cell activation in allergic pulmonary inflammation. Journal of Immunology, vol.187(3): 1486–1495.

Tsukimoto M, Tokunaga A, Harada H, et al. 2009, Blockade of murine T cell activation by antagonists of P2Y6 and P2X7 receptors. Biochemical Biophysical Research Communication, vol.384(4): 512–518.

Inaba K, Inaba M, Romani N, et al. 1992, Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. Journal of Experimental Medicine, vol.176(6): 1693–1702.

Ben Addi A, Lefort A, Hua X, et al. 2008, Modulation of murine dendritic cell function by adenine nucleotides and adenosine: involvement of the A(2B) receptor. European Journal of Immunology, vol.38(6): 1610–1620.

Norbury C C, 2006, Drinking a lot is good for dendritic cells. Immunology, vol.117(4): 443–451.

Burgdorf S, Kautz A, Böhnert V, et al. 2007, Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science, vol.316(5824): 612–616.

Marteau F, Communi D, Boeynaems J M, et al. 2004, Involvement of multiple P2Y receptors and signaling pathways in the action of adenine nucleotides diphosphates on human monocyte-derived dendritic cells. Journal of Leukocyte Biology, vol.76(4): 796–803.

Wilkin F, Duhant X, Bruyns C, et al. 2001, The P2Y11 receptor mediates the ATP-induced maturation of human monocyte-derived dendritic cells. Journal of Immunology, vol.166(12): 7172–7177.

Wilkin F, Stordeur P, Goldman M, et al. 2002, Extracellular adenine nucleotides modulate cytokine production by human monocyte-derived dendritic cells: dual effect on IL-12 and stimulation of IL-10. European Journal of Immunology, vol.32(9): 2409–2417.;2-H

Müller T, Robaye B, Vieira R P, et al. 2010, The purinergic receptor P2Y2 receptor mediates chemotaxis of dendritic cells and eosinophils in allergic lung inflammation. Allergy, vol.65(12): 1545–1553.

Pizzirani C, Ferrari D, Chiozzi P, et al. 2007, Stimulation of P2 receptors causes release of IL-1β-loaded microve-sicles from human dendritic cells. Blood, vol.109: 3856–3864.

Weber F C, Esser P R, Müller T, et al. 2010, Lack of the purinergic receptor P2X7 results in resistance to contact hypersensitivity. Journal of Experimental Medicine, vol.207(12): 2609–2619.

Cunningham A F, Khan M, Ball J, et al. 2004, Responses to the soluble flagellar protein FliC are Th2, while those to FliC on Salmonella are Th1. European Journal of Immunology, vol.34(11): 2986–2995.

(691 Abstract Views, 469 PDF Downloads)


  • There are currently no refbacks.

Copyright (c) 2016 Dorothée Cammarata1, Abduelhakem Ben Addi, Eva D’Amico, Bernard Robaye

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.