P2Y6 Receptor Antagonist MRS2578 Inhibits Neutrophil Activation and Aggregated Neutrophil Extracellular Trap Formation Induced by Gout-Associated Monosodium Urate Crystals
Tóm tắt
Human neutrophils (polymorphonuclear leukocytes [PMNs]) generate inflammatory responses within the joints of gout patients upon encountering monosodium urate (MSU) crystals. Neutrophil extracellular traps (NETs) are found abundantly in the synovial fluid of gout patients. The detailed mechanism of MSU crystal–induced NET formation remains unknown. Our goal was to shed light on possible roles of purinergic signaling and neutrophil migration in mediating NET formation induced by MSU crystals. Interaction of human neutrophils with MSU crystals was evaluated by high-throughput live imaging using confocal microscopy. We quantitated NET levels in gout synovial fluid supernatants and detected enzymatically active neutrophil primary granule enzymes, myeloperoxidase, and human neutrophil elastase. Suramin and PPADS, general P2Y receptor blockers, and MRS2578, an inhibitor of the purinergic P2Y6 receptor, blocked NET formation triggered by MSU crystals. AR-C25118925XX (P2Y2 antagonist) did not inhibit MSU crystal–stimulated NET release. Live imaging of PMNs showed that MRS2578 represses neutrophil migration and blocked characteristic formation of MSU crystal–NET aggregates called aggregated NETs. Interestingly, the store-operated calcium entry channel inhibitor (SK&F96365) also reduced MSU crystal–induced NET release. Our results indicate that the P2Y6/store-operated calcium entry/IL-8 axis is involved in MSU crystal–induced aggregated NET formation, but MRS2578 could have additional effects affecting PMN migration. The work presented in the present study could lead to a better understanding of gouty joint inflammation and help improve the treatment and care of gout patients.
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Kuo, 2015, Global epidemiology of gout: prevalence, incidence and risk factors., Nat. Rev. Rheumatol., 11, 649, 10.1038/nrrheum.2015.91
Abbott, 2005, New-onset gout after kidney transplantation: incidence, risk factors and implications., Transplantation, 80, 1383, 10.1097/01.tp.0000188722.84775.af
Abbott, 1988, Gout and coronary heart disease: the Framingham Study., J. Clin. Epidemiol., 41, 237, 10.1016/0895-4356(88)90127-8
Ask-Upmark, 1951, Coronary infarction and gout., Acta Med. Scand., 139, 1, 10.1111/j.0954-6820.1950.tb17139.x
Schauer, 2014, Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines., Nat. Med., 20, 511, 10.1038/nm.3547
Mitroulis, 2011, Neutrophil extracellular trap formation is associated with IL-1β and autophagy-related signaling in gout., PLoS One, 6, e29318, 10.1371/journal.pone.0029318
Mitroulis, 2013, Neutrophils, IL-1β, and gout: is there a link?, Semin. Immunopathol., 35, 501, 10.1007/s00281-013-0361-0
So, 2007, [Recent advances in the pathophysiology of hyperuricemia and gout], Rev. Med. Suisse, 3, 720–, 722
So, 2010, Epidemiology: gout—bad for the heart as well as the joint., Nat. Rev. Rheumatol., 6, 386, 10.1038/nrrheum.2010.78
So, 2008, Developments in the scientific and clinical understanding of gout., Arthritis Res. Ther., 10, 221, 10.1186/ar2509
Busso, 2012, The mechanisms of inflammation in gout and pseudogout (CPP-induced arthritis)., Reumatismo, 63, 230, 10.4081/reumatismo.2011.230
Martinon, 2006, Gout-associated uric acid crystals activate the NALP3 inflammasome., Nature, 440, 237, 10.1038/nature04516
Pétrilli, 2007, The inflammasome, autoinflammatory diseases, and gout., Joint Bone Spine, 74, 571, 10.1016/j.jbspin.2007.04.004
Oliveira, 2008, Neutrophil migration induced by IL-1β depends upon LTB4 released by macrophages and upon TNF-α and IL-1β released by mast cells., Inflammation, 31, 36, 10.1007/s10753-007-9047-x
Brinkmann, 2007, Beneficial suicide: why neutrophils die to make NETs., Nat. Rev. Microbiol., 5, 577, 10.1038/nrmicro1710
Brinkmann, 2012, Neutrophil extracellular traps: is immunity the second function of chromatin?, J. Cell Biol., 198, 773, 10.1083/jcb.201203170
Brinkmann, 2004, Neutrophil extracellular traps kill bacteria., Science, 303, 1532, 10.1126/science.1092385
Fuchs, 2007, Novel cell death program leads to neutrophil extracellular traps., J. Cell Biol., 176, 231, 10.1083/jcb.200606027
Grayson, 2016, At the Bench: neutrophil extracellular traps (NETs) highlight novel aspects of innate immune system involvement in autoimmune diseases., J. Leukoc. Biol., 99, 253, 10.1189/jlb.5BT0615-247R
Stoiber, 2015, The role of reactive oxygen species (ROS) in the formation of extracellular traps (ETs) in humans., Biomolecules, 5, 702, 10.3390/biom5020702
Wang, 2014, Regulation of immune responses by neutrophils., Ann. N. Y. Acad. Sci., 1319, 66, 10.1111/nyas.12445
Christine Czegley, 2014, Monocytes and granulocytes orchestrate induction and resolution of inflammation in gout., Gout Hyperuricemia, 1, 88
Desai, 2016, PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling., Eur. J. Immunol., 46, 223, 10.1002/eji.201545605
Uratsuji, 2012, P2Y6 receptor signaling pathway mediates inflammatory responses induced by monosodium urate crystals., J. Immunol., 188, 436, 10.4049/jimmunol.1003746
Abbracchio, 2006, International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy., Pharmacol. Rev., 58, 281, 10.1124/pr.58.3.3
von Kugelgen, 2016, Pharmacology and structure of P2Y receptors., Neuropharmacology., 50, 10.1016/j.neuropharm.2015.10.030
Junger, 2011, Immune cell regulation by autocrine purinergic signalling., Nat. Rev. Immunol., 11, 201, 10.1038/nri2938
Taylor, 2008, A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic gout. [Published erratum appears in 2006 Ann. Rheum. Dis. 67: 1652.], Ann. Rheum. Dis., 67, 888, 10.1136/ard.2007.079970
Grassi, 2010, Purinergic control of neutrophil activation., J. Mol. Cell Biol., 2, 176, 10.1093/jmcb/mjq014
Hidalgo, 2015, fMLP-induced IL-8 release is dependent on NADPH oxidase in human neutrophils., J. Immunol. Res., 2015, 120348, 10.1155/2015/120348
Campwala, 2014, P2Y6 receptor inhibition perturbs CCL2-evoked signalling in human monocytic and peripheral blood mononuclear cells., J. Cell Sci., 127, 4964
Grbic, 2008, Intestinal inflammation increases the expression of the P2Y6 receptor on epithelial cells and the release of CXC chemokine ligand 8 by UDP., J. Immunol., 180, 2659, 10.4049/jimmunol.180.4.2659
Khine, 2006, Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway., Blood, 107, 2936, 10.1182/blood-2005-06-2314
Xiang, 2006, Distribution of P2Y6 and P2Y12 receptor: their colocalization with calbindin, calretinin and nitric oxide synthase in the guinea pig enteric nervous system., Histochem. Cell Biol., 125, 327, 10.1007/s00418-005-0071-3
Schreiber, 2005, Purinergic P2Y6 receptors induce Ca2+ and CFTR dependent Cl− secretion in mouse trachea., Cell. Physiol. Biochem., 16, 99, 10.1159/000087736
Cox, 2005, The pyrimidinergic P2Y6 receptor mediates a novel release of proinflammatory cytokines and chemokines in monocytic cells stimulated with UDP., Biochem. Biophys. Res. Commun., 330, 467, 10.1016/j.bbrc.2005.03.004
Korcok, 2005, P2Y6 nucleotide receptors activate NF-κB and increase survival of osteoclasts., J. Biol. Chem., 280, 16909, 10.1074/jbc.M410764200
Hansen, 2013, The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction., PLoS One, 8, e81491, 10.1371/journal.pone.0081491
Liu, 2009, P2Y6 receptor and immunoinflammation., Neurosci. Bull., 25, 161, 10.1007/s12264-009-0120-3
Yoo, 2014, NET formation induced by Pseudomonas aeruginosa cystic fibrosis isolates measured as release of myeloperoxidase–DNA and neutrophil elastase–DNA complexes., Immunol. Lett., 160, 186, 10.1016/j.imlet.2014.03.003
Yoo, 2014, Release of cystic fibrosis airway inflammatory markers from Pseudomonas aeruginosa–stimulated human neutrophils involves NADPH oxidase-dependent extracellular DNA trap formation., J. Immunol., 192, 4728, 10.4049/jimmunol.1301589
Altman, 1986, Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee., Arthritis Rheum., 29, 1039, 10.1002/art.1780290816
Pang, 2013, Pseudogout-associated inflammatory calcium pyrophosphate dihydrate microcrystals induce formation of neutrophil extracellular traps., J. Immunol., 190, 6488, 10.4049/jimmunol.1203215
Sil P., Yoo D. G., Floyd M., Gingerich A., Rada B.. 2016. High throughput measurement of extracellular DNA release and quantitative NET formation in human neutrophils in vitro. J. Vis. Exp. 112: e52779. Available at: https://www.jove.com/video/52779/high-throughput-measurement-extracellular-dna-release-quantitative.
Watford, 2006, Cytohesin binder and regulator (Cybr) is not essential for T- and dendritic-cell activation and differentiation., Mol. Cell. Biol., 26, 6623, 10.1128/MCB.02460-05
Zhang, 2013, Aggrecanases in the human synovial fluid at different stages of osteoarthritis., Clin. Rheumatol., 32, 797, 10.1007/s10067-013-2171-0
Robinson, 2016, Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis., Nat. Rev. Rheumatol., 12, 580, 10.1038/nrrheum.2016.136
Popa-Nita, 2010, Crystal-induced neutrophil activation., Immunol. Cell Biol., 88, 32, 10.1038/icb.2009.98
Carulli, 1985, Modifications in the phagocytosis of human neutrophils induced by vinblastine and cytochalasin B: the effects of lithium., Acta Haematol., 74, 81, 10.1159/000206173
Chen, 2010, Purinergic signaling: a fundamental mechanism in neutrophil activation., Sci. Signal., 3, ra45, 10.1126/scisignal.2000549
Laubinger, 2003, P2Y receptor specific for diadenosine tetraphosphate in lung: selective inhibition by suramin, PPADS, Ip5I, and not by MRS-2197., Eur. J. Pharmacol., 468, 9, 10.1016/S0014-2999(03)01624-8
Charlton, 1996, PPADS and suramin as antagonists at cloned P2Y- and P2U-purinoceptors., Br. J. Pharmacol., 118, 704, 10.1111/j.1476-5381.1996.tb15457.x
Usune, 1996, Effects of PPADS and suramin on contractions and cytoplasmic Ca2+ changes evoked by AP4A, ATP and α,β-methylene ATP in guinea-pig urinary bladder., Br. J. Pharmacol., 117, 698, 10.1111/j.1476-5381.1996.tb15246.x
Lewis R. S. 2011. Store-operated calcium channels: new perspectives on mechanism and function. Cold Spring Harb. Perspect. Biol. 3: a003970. Available at: http://cshperspectives.cshlp.org/content/3/12/a003970.full.
Braganhol, 2015, Nucleotide receptors control IL-8/CXCL8 and MCP-1/CCL2 secretions as well as proliferation in human glioma cells., Biochim. Biophys. Acta, 1852, 120, 10.1016/j.bbadis.2014.10.014
Mély, 1997, Mapping the suramin-binding sites of human neutrophil elastase: investigation by fluorescence resonance energy transfer and molecular modeling., Biochemistry, 36, 15624, 10.1021/bi971029r
Cadène, 1997, Inhibition of neutrophil serine proteinases by suramin., J. Biol. Chem., 272, 9950, 10.1074/jbc.272.15.9950
Metzler, 2014, A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis., Cell Rep., 8, 883, 10.1016/j.celrep.2014.06.044
Papayannopoulos, 2010, Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps., J. Cell Biol., 191, 677, 10.1083/jcb.201006052
Martinod, 2016, Neutrophil elastase-deficient mice form neutrophil extracellular traps in an experimental model of deep vein thrombosis., J. Thromb. Haemost., 14, 551, 10.1111/jth.13239
Crocetti, 2013, Optimization of N-benzoylindazole derivatives as inhibitors of human neutrophil elastase., J. Med. Chem., 56, 6259, 10.1021/jm400742j
El-Tayeb, 2006, Synthesis and structure–activity relationships of uracil nucleotide derivatives and analogues as agonists at human P2Y2, P2Y4, and P2Y6 receptors., J. Med. Chem., 49, 7076, 10.1021/jm060848j
Ko, 2008, Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists., Bioorg. Med. Chem., 16, 6319, 10.1016/j.bmc.2008.05.013
Önnheim, 2014, A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide., Exp. Cell Res., 323, 209, 10.1016/j.yexcr.2014.01.023
Jacob, 2013, Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses., Purinergic Signal., 9, 285, 10.1007/s11302-013-9357-4
Mamedova, 2004, Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y6 nucleotide receptors., Biochem. Pharmacol., 67, 1763, 10.1016/j.bcp.2004.01.011
Nagaoka, 2010, Evaluation of the effect of α-defensin human neutrophil peptides on neutrophil apoptosis., Int. J. Mol. Med., 26, 925, 10.3892/ijmm_00000544
Yu, 2013, Lack of specificity shown by P2Y6 receptor antibodies., Naunyn Schmiedebergs Arch. Pharmacol., 386, 885, 10.1007/s00210-013-0894-8
Cekic, 2016, Purinergic regulation of the immune system., Nat. Rev. Immunol., 16, 177, 10.1038/nri.2016.4
Chen, 2014, The role of nucleotides and purinergic signaling in apoptotic cell clearance—implications for chronic inflammatory diseases., Front. Immunol., 5, 656, 10.3389/fimmu.2014.00656
Ginsburg-Shmuel, 2012, UDP made a highly promising stable, potent, and selective P2Y6-receptor agonist upon introduction of a boranophosphate moiety., Bioorg. Med. Chem., 20, 5483, 10.1016/j.bmc.2012.07.042
Koizumi, 2007, UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis., Nature, 446, 1091, 10.1038/nature05704
Neher, 2014, Inhibition of UDP/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo., Glia, 62, 1463, 10.1002/glia.22693
Keshari, 2012, Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition., PLoS One, 7, e48111, 10.1371/journal.pone.0048111
Hazeldine, 2014, Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals., Aging Cell, 13, 690, 10.1111/acel.12222
Rada, 2004, Dual role of phagocytic NADPH oxidase in bacterial killing., Blood, 104, 2947, 10.1182/blood-2004-03-1005
Rada, 2013, Pyocyanin-enhanced neutrophil extracellular trap formation requires the NADPH oxidase., PLoS One, 8, e54205, 10.1371/journal.pone.0054205
Zizzo, 2012, Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum., Purinergic Signal., 8, 275, 10.1007/s11302-011-9281-4
Douda, 2015, SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx., Proc. Natl. Acad. Sci. USA, 112, 2817, 10.1073/pnas.1414055112
Grbic, 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., Inflamm. Bowel Dis., 18, 1456, 10.1002/ibd.21931
Ide, 2014, Purine receptor P2Y6 mediates cellular response to γ-ray-induced DNA damage., J. Toxicol. Sci., 39, 15, 10.2131/jts.39.15
Inoue, 2007, UDP facilitates microglial phagocytosis through P2Y6 receptors., Cell Adhes. Migr., 1, 131, 10.4161/cam.1.3.4937
Rada, 2003, Calcium signalling is altered in myeloid cells with a deficiency in NADPH oxidase activity., Clin. Exp. Immunol., 132, 53, 10.1046/j.1365-2249.2003.02138.x
Clemens, 2015, Store-operated calcium signaling in neutrophils., J. Leukoc. Biol., 98, 497, 10.1189/jlb.2MR1114-573R
Travis, 1988, Structure, function, and control of neutrophil proteinases., Am. J. Med., 84, 37, 10.1016/S0002-9343(88)80068-8
Watorek, 1988, Neutrophil elastase and cathepsin G: structure, function, and biological control., Adv. Exp. Med. Biol., 240, 23, 10.1007/978-1-4613-1057-0_3
Amitani, 1991, Effects of human neutrophil elastase and Pseudomonas aeruginosa proteinases on human respiratory epithelium., Am. J. Respir. Cell Mol. Biol., 4, 26, 10.1165/ajrcmb/4.1.26
Lucey, 1985, Effect of combined human neutrophil cathepsin G and elastase on induction of secretory cell metaplasia and emphysema in hamsters, with in vitro observations on elastolysis by these enzymes., Am. Rev. Respir. Dis., 132, 362
Smallman, 1984, Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect., Thorax, 39, 663, 10.1136/thx.39.9.663
Sly, 2013, Risk factors for bronchiectasis in children with cystic fibrosis., N. Engl. J. Med., 368, 1963, 10.1056/NEJMoa1301725
Hoenderdos, 2013, The neutrophil in chronic obstructive pulmonary disease., Am. J. Respir. Cell Mol. Biol., 48, 531, 10.1165/rcmb.2012-0492TR
Sandhaus, 2013, Neutrophil elastase-mediated lung disease., COPD, 10, 60, 10.3109/15412555.2013.764403
Neogi, 2015, 2015 Gout classification criteria: an American College of Rheumatology/European League against Rheumatism collaborative initiative. [Published erratum appears in 2016 Ann. Rheum. Dis. 75: 473.], Ann. Rheum. Dis., 74, 1789, 10.1136/annrheumdis-2015-208237
Ogdie, 2015, Imaging modalities for the classification of gout: systematic literature review and meta-analysis., Ann. Rheum. Dis., 74, 1868, 10.1136/annrheumdis-2014-205431
Taylor, 2015, Study for updated gout classification criteria: identification of features to classify gout., Arthritis Care Res. (Hoboken), 67, 1304, 10.1002/acr.22585
Schorn, 2012, Monosodium urate crystals induce extracellular DNA traps in neutrophils, eosinophils, and basophils but not in mononuclear cells., Front. Immunol., 3, 277, 10.3389/fimmu.2012.00277
Arai, 2013, Uric acid induces NADPH oxidase-independent neutrophil extracellular trap formation., Biochem. Biophys. Res. Commun.
Dahl, 2015, ATP release through pannexon channels., Philos. Trans. R. Soc. Lond. B Biol. Sci., 370, 370, 10.1098/rstb.2014.0191
Hoyle, 1990, Suramin antagonizes responses to P2-purinoceptor agonists and purinergic nerve stimulation in the guinea-pig urinary bladder and taenia coli., Br. J. Pharmacol., 99, 617, 10.1111/j.1476-5381.1990.tb12979.x
Ralevic, 1996, Discrimination by PPADS between endothelial P2Y- and P2U-purinoceptors in the rat isolated mesenteric arterial bed., Br. J. Pharmacol., 118, 428, 10.1111/j.1476-5381.1996.tb15420.x
Li, 2014, Extracellular UDP and P2Y6 function as a danger signal to protect mice from vesicular stomatitis virus infection through an increase in IFN-β production., J. Immunol., 193, 4515, 10.4049/jimmunol.1301930
Kukulski, 2007, Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo., J. Leukoc. Biol., 81, 1269, 10.1189/jlb.1206758
Ibusuki, 2015, Human neutrophil peptides induce interleukin-8 in intestinal epithelial cells through the P2 receptor and ERK1/2 signaling pathways., Int. J. Mol. Med., 35, 1603, 10.3892/ijmm.2015.2156
Syhr, 2014, Lack of effect of a P2Y6 receptor antagonist on neuropathic pain behavior in mice., Pharmacol. Biochem. Behav., 124, 389, 10.1016/j.pbb.2014.07.009
Zhang, 2011, P2Y6 agonist uridine 5′-diphosphate promotes host defense against bacterial infection via monocyte chemoattractant protein-1-mediated monocytes/macrophages recruitment., J. Immunol., 186, 5376, 10.4049/jimmunol.1002946
Itagaki, 2002, Store-operated calcium entry in human neutrophils reflects multiple contributions from independently regulated pathways., J. Immunol., 168, 4063, 10.4049/jimmunol.168.8.4063
Demaurex, 2016, The role of STIM and ORAI proteins in phagocytic immune cells, Am. J. Physiol. Cell. Physiol., 310, C496, 10.1152/ajpcell.00360.2015
Dixit, 2012, Chemokines, selectins and intracellular calcium flux: temporal and spatial cues for leukocyte arrest., Front. Immunol., 3, 188, 10.3389/fimmu.2012.00188
Michaelis, 2015, STIM1, STIM2, and Orai1 regulate store-operated calcium entry and purinergic activation of microglia., Glia, 63, 652, 10.1002/glia.22775
Zhang, 2014, STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense., Blood, 123, 2238, 10.1182/blood-2012-08-450403
Almasi, 2013, Quantitative evaluation of CXCL8 and its receptors (CXCR1 and CXCR2) gene expression in Iranian patients with multiple sclerosis., Immunol. Invest., 42, 737, 10.3109/08820139.2013.812652
Reyes-Robles, 2013, Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection., Cell Host Microbe, 14, 453, 10.1016/j.chom.2013.09.005
Alonzo, 2013, CCR5 is a receptor for Staphylococcus aureus leukotoxin ED., Nature, 493, 51, 10.1038/nature11724
Jones, 2009, Protein arginine deiminase 4 (PAD4): current understanding and future therapeutic potential., Curr. Opin. Drug Discov. Devel., 12, 616
Gupta, 2014, Efficient neutrophil extracellular trap induction requires mobilization of both intracellular and extracellular calcium pools and is modulated by cyclosporine A., PLoS One, 9, e97088, 10.1371/journal.pone.0097088