Purinergic signaling and immune cell chemotaxis . Focus on “The UDP-sugar-sensing P2Y 14 receptor promotes Rho-mediated signaling and chemotaxis in human neutrophils”
2012; American Physical Society; Volume: 303; Issue: 5 Linguagem: Inglês
10.1152/ajpcell.00184.2012
ISSN1522-1563
Autores Tópico(s)Receptor Mechanisms and Signaling
ResumoEditorial FocusPurinergic signaling and immune cell chemotaxis. Focus on "The UDP-sugar-sensing P2Y14 receptor promotes Rho-mediated signaling and chemotaxis in human neutrophils"Scott M. O'GradyScott M. O'GradyDepartments of Animal Science and Integrative Biology and Physiology, University of Minnesota, St. Paul, MinnesotaPublished Online:01 Sep 2012https://doi.org/10.1152/ajpcell.00184.2012This is the final version - click for previous versionMoreSectionsPDF (142 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat purinergic receptors enable cells to detect and respond to extracellular nucleotides and adenosine. Presently, eight G protein-coupled P2Y receptors, four adenosine receptors, and seven ionotropic P2X receptors have been cloned and characterized (11). In addition, multiple ectonucleotidases and pathways for nucleotide release have been identified in mammalian cells where they function collaboratively within signaling complexes to regulate a variety of physiologic process (2). In immune cells, these complexes facilitate recognition of nucleotides released from damaged or stressed cells, which in turn triggers autocrine purinergic feedback pathways that promote recruitment and inflammatory responses at the site of infection (3, 6). Interactions between paracrine and autocrine purinergic signaling mechanisms allows immune cells to modify their response to danger signals and find-me cues released by surrounding tissues. Purinoceptor stimulation also activates inflammasomes, resulting in secretion of cytokines that contribute to the overall inflammatory response (6).Overview of neutrophil recruitment and chemotaxis.Neutrophils are polymorphonuclear leukocytes that are stored in bone marrow then rapidly released into the circulation in response to infection. They can be recruited from the blood stream into affected tissues by various chemoattractant molecules produced by microorganisms or by host cells within infected and inflamed tissues. Neutrophil extravasation initially involves adhesion to the endothelium, a process that is mediated by P-selectin ligand-1 (PSGL-1) located at the tips of neutrophil microvilli. PSGL-1 binds to P-selectin to produce tethering and rolling of neutrophils along the endothelium of the microcirculation (6). Exposure to chemotactic molecules under these conditions results in expression of integrins on the cell surface that strengthens neutrophil adherence to endothelial cells. Transmigration then occurs through paracellular or transcellular pathways without damaging endothelial integrity. Once neutrophils enter the extravascular space they migrate towards the source of chemotactic mediators released from the site of inflammation or tissue damage. The widely accepted local excitation, global inhibition model for gradient sensing and chemotaxis suggests that a combination of leading edge positive feedback loops and longer range negative feedback mechanisms translate and amplify weak extracellular chemoattractant gradients into well-defined internal signals that direct pseudopod protrusion at the leading edge while suppressing signals that would yield protrusions along the lateral and trailing margins of polarized cells (6).Autocrine purinergic signaling and modulation of the chemotactic response.Activation of chemoattractant receptors expressed by neutrophils evokes the polarized release and accumulation of ATP at the cell surface nearest to the chemoattractant source (3, 7). P2Y2 receptors adjacent to the site of release become activated and amplify intracellular signals initially generated by chemoreceptor stimulation. As neutrophils undergo polarization, proteins involved in purinergic signaling such as pannexin 1 (channels through which ATP is released), the ectonucleotidase CD39 and A3 adenosine receptors redistribute to the leading edge of the cell. Additional ATP release associated with lamellipodia protrusion is hydrolyzed by CD39 to produce adenosine, which binds to A3 receptors to strengthen purinergic feedback pathways necessary for migration towards the chemoattractant source (Fig. 1). Negative, longer range autocrine purinoceptor feedback mediated by A2A adenosine receptors blocks cell activation at sites away from the leading edge of the cell and supports cell migration by promoting retraction at the trailing edge (7). Thus autocrine purinergic feedback loops represent a specific example of local excitation, global inhibition that modulates the chemotactic response of neutrophils initiated by chemoattractants emanating from a site of infection or inflammation.Fig. 1.Proposed model for autocrine purinergic signaling and modulation of chemoattractant activated motility in neutrophils. [Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology (Ref. 7, Fig. 2), copyright 2011.]Download figureDownload PowerPointUDP-glucose and P2Y14 receptor-mediated neutrophil motility.The present study by Sesma et al., published in this issue of the American Journal of Physiology-Cell Physiology (10), investigated the role of P2Y14 receptors (P2Y14-R) in neutrophil chemotaxis. P2Y14-R is a Gi-coupled receptor that is activated by UDP and UDP-sugars, but not by UTP, ATP, ADP, or other naturally occurring nucleotide di- or triphosphates. Earlier studies showed that UDP-glucose is released with mucins from the airway epithelium by exocytosis under conditions of inflammation and unlike ATP or UTP, extracellular UDP-glucose is stable and not readily degraded by ectonucleotidases (10). UDP-glucose was also found to stimulate alveolar and airway epithelial cells to secrete proinflammatory chemokines capable of inducing neutrophil recruitment (8). Results from Sesma et al. (10) demonstrate that UDP-glucose functions as a stable chemoattractant for neutrophils in response to tissue damage or inflammation. In addition, chemotaxis was partially inhibited when neutrophils and differentiated HL60 cells were treated with apyrase, suggesting that ATP release was associated with UDP-glucose stimulation (10).Neutrophil exposure to UDP-glucose induced RhoA activation, rearrangement of the cytoskeleton and stimulated cell migration. Treatment with Rho kinase inhibitors decreased migration, which is consistent with previously published data showing that Rho kinase activation is associated with cell polarization along the axis of movement and myosin-dependent retraction of the trailing edge of the cell. The proposed mechanism of RhoA activation evoked by UDP-glucose binding to P2Y14-R appears to involve pertussis toxin-sensitive Gi activation and subsequent Gβγ-induced increases in phosphoinositide 3-kinase (PI-3-kinase) activity. The resulting stimulation of phosphatidylinositol(3,4,5)trisphosphate production facilitates Rho-G protein exchange factor recruitment to the plasma membrane and enhanced RhoGTP formation, similar to fMLP receptor signaling in other immune cells (1).Implications.An issue that was not addressed by Sesma et al. (10) involves the cellular localization of P2Y14-R and whether its distribution changes in response to the presence of a gradient for UDP-sugars. This would have implications for gradient amplification since chemoattractant receptors have been reported to redistribute to the leading edge of the cell during polarization and migration. P2Y14-R redistribution may coincide with activation and recruitment of PI-3 kinase and the movement of lipid rafts to the leading edge of the cell. Asymmetric redistribution of lipid rafts has been shown to occur following stimulation with chemoattractants and electric fields. Interestingly, treatment of DMSO-differentiated HL60 cells with pertussis toxin inhibits raft redistribution in response to stimulation with fMLP, suggesting that rafts function as signal amplification platforms during chemotaxis (5). Based on the results of Sesma et al. (10), the post-receptor signaling events associated with P2Y14-R could facilitate trafficking of receptor-containing rafts to the leading edge to enhance UDP-sugar detection.Although a specific role for P2Y14-R in autocrine modulation of neutrophil chemotaxis was not specifically identified by Sesma et al. (10), previous studies have shown that UDP functions as a P2Y14-R agonist (4). Therefore, it is conceivable that UTP release from neutrophils and subsequent CD39-mediated UDP accumulation at the leading edge during lamellipodia protrusion could activate P2Y14-R (and potentially P2Y6-R) to provide local amplification of intracellular signals originally produced in response to a chemoattractant gradient. Moreover, in addition to the previously described role for Gq-coupled P2Y2 receptors in chemoattractant signal amplification, Gi activation following UDP binding to P2Y14-R would presumably broaden the array of post-receptor signaling pathways that would be activated by autocrine ATP and UTP release. Ultimately, it may be that P2Y14-R functions as both a primary chemoattractant detection mechanism for UDP sugars and as a component of autocrine purinergic signaling responsible for modulation of the neutrophil chemotactic response.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author.AUTHOR CONTRIBUTIONSS.M.O. prepared the figure; drafted the manuscript; edited and revised the manuscript; and approved the final version of the manuscript.REFERENCES1. Chen LY , Zuraw BL , Ye RD , Pan ZK . A Rho exchange factor mediates fMet-Leu-Phe-induced NF-kappaB activation in human peripheral blood monocytes. J Biol Chem 279: 7208– 7212, 2004.Crossref | PubMed | ISI | Google Scholar2. Corriden R , Chen Y , Inoue Y , Beldi G , Robson SC , Insel PA , Junger WG . Ecto-nucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1/CD39) regulates neutrophil chemotaxis by hydrolyzing released ATP to adenosine. J Biol Chem 283: 28480– 28486, 2008.Crossref | PubMed | ISI | Google Scholar3. Corriden R , Insel PA . New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors. Purinergic Signal 8: 587– 598, 2012.Crossref | PubMed | ISI | Google Scholar4. Das A , Ko H , Burianek LE , Barrett MO , Harden TK , Jacobson KA . Human P2Y14 receptor agonists: truncation of the hexose moiety of uridine-5′-diphosphoglucose and its replacement with alkyl and aryl groups. J Med Chem 53: 471– 480, 2010.Crossref | PubMed | ISI | Google Scholar5. Gomez-Mouton C , Lacalle RA , Mira E , Jimenez-Baranda S , Barber DF , Carrera AC , Martinez- AC , Manes S . Dynamic redistribution of raft domains as an organizing platform for signaling during cell chemotaxis. J Cell Biol 164: 759– 768, 2004.Crossref | PubMed | ISI | Google Scholar6. Junger WG . Purinergic regulation of neutrophil chemotaxis. Cell Mol Life Sci 65: 2528– 2540, 2008.Crossref | PubMed | ISI | Google Scholar7. Junger WG . Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol 11: 201– 212, 2011.Crossref | PubMed | ISI | Google Scholar8. Muller T , Bayer H , Myrtek D , Ferrari D , Sorichter S , Ziegenhagen MW , Zissel G , Virchow JC , Luttmann W , Norgauer J , Di Virgilio F , Idzko M . The P2Y14 receptor of airway epithelial cells: coupling to intracellular Ca2+ and IL-8 secretion. Am J Respir Cell Mol Biol 33: 601– 609, 2005.Crossref | PubMed | ISI | Google Scholar9. Sesma JI , Esther CR , Kreda SM , Jones L , O'Neal W , Nishihara S , Nicholas RA , Lazarowski ER . Endoplasmic reticulum/golgi nucleotide sugar transporters contribute to the cellular release of UDP-sugar signaling molecules. J Biol Chem 284: 12572– 12583, 2009.Crossref | PubMed | ISI | Google Scholar10. Sesma JI , Kreda SM , Steinckwich-Besancon N , Dang H , García-Mata R , Harden TK , Lazarowski ER . The UDP-sugar-sensing P2Y14 receptor promotes Rho-mediated signaling and chemotaxis in human neutrophils. Am J Physiol Cell Physiol (June 6, 2012). doi:https://doi.org/10.1152/ajpcell.00138.2012.Link | ISI | Google Scholar11. Von Kugelgen I , Harden TK . Molecular pharmacology, physiology, and structure of the P2Y receptors. Adv Pharmacol 61: 373– 415, 2011.Crossref | PubMed | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: S. M. O'Grady, Depts. of Animal Science and Integrative Biology and Physiology, Univ. of Minnesota, 1364 Eckles Ave., St. Paul, MN 55108 (e-mail: [email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByPurinergic Signaling During Immune Cell TraffickingTrends in Immunology, Vol. 37, No. 6Purinergic signalling and immune cells29 October 2014 | Purinergic Signalling, Vol. 10, No. 4Characterization of the contractile P2Y14 receptor in mouse coronary and cerebral arteries6 June 2014 | FEBS Letters, Vol. 588, No. 17The UDP-sugar-sensing P2Y14 receptor promotes Rho-mediated signaling and chemotaxis in human neutrophilsJuliana I. Sesma, Silvia M. Kreda, Natacha Steinckwich-Besancon, Hong Dang, Rafael García-Mata, T. Kendall Harden, and Eduardo R. Lazarowski1 September 2012 | American Journal of Physiology-Cell Physiology, Vol. 303, No. 5 More from this issue > Volume 303Issue 5September 2012Pages C486-C487 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00184.2012PubMed22673620History Published online 1 September 2012 Published in print 1 September 2012 Metrics
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