{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T02:42:00Z","timestamp":1783392120740,"version":"3.54.6"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2017-06116"],"award-info":[{"award-number":["RGPIN-2017-06116"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000142","name":"Arthritis Society","doi-asserted-by":"publisher","award":["SOG-10-0475"],"award-info":[{"award-number":["SOG-10-0475"]}],"id":[{"id":"10.13039\/501100000142","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Purinergic signaling plays a major role in T cell activation leading to IL-2 production and proliferation. However, it is unclear whether purinergic signaling contributes to the differentiation and activation of effector T cells. In this study, we found that the purinergic receptor P2X4 was associated with human Th17 cells but not with Th1 cells. Inhibition of P2X4 receptor with the specific antagonist 5-BDBD and small interfering RNA inhibited the development of Th17 cells and the production of IL-17 by effector Th17 cells stimulated via the CD3\/CD28 pathway. Our results showed that P2X4 was required for the expression of retinoic acid-related orphan receptor C, which is the master regulator of Th17 cells. In contrast, inhibition of P2X4 receptor had no effect on Th1 cells and on the production of IFN-\u03b3 and it did not affect the expression of the transcription factor T-bet (T-box transcription factor). Furthermore, inhibition of P2X4 receptor reduced the production of IL-17 but not of IFN-\u03b3 by effector\/memory CD4+ T cells isolated from patients with rheumatoid arthritis. In contrast to P2X4, inhibition of P2X7 and P2Y11 receptors had no effects on Th17 and Th1 cell activation. Finally, treatment with the P2X4 receptor antagonist 5-BDBD reduced the severity of collagen-induced arthritis in mice by inhibiting Th17 cell expansion and activation. Our findings provide novel insights into the role of purinergic signaling in T cell activation and identify a critical role for the purinergic receptor P2X4 in Th17 activation and in autoimmune arthritis.<\/jats:p>","DOI":"10.4049\/jimmunol.2100550","type":"journal-article","created":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T15:50:29Z","timestamp":1644853829000},"page":"1115-1127","source":"Crossref","is-referenced-by-count":18,"title":["The Purinergic Receptor P2X4 Promotes Th17 Activation and the Development of Arthritis"],"prefix":"10.1093","volume":"208","author":[{"given":"Chakib","family":"Hamoudi","sequence":"first","affiliation":[{"name":"Division of Immune and Infectious Diseases, CHU de Qu\u00e9bec Research Center , Quebec City, Quebec,","place":["Canada"]},{"name":"ARThrite Center, Laval University , Quebec City, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenqi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Immune and Infectious Diseases, CHU de Qu\u00e9bec Research Center , Quebec City, Quebec,","place":["Canada"]},{"name":"ARThrite Center, Laval University , Quebec City, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amna","family":"Abderrazak","sequence":"additional","affiliation":[{"name":"Division of Immune and Infectious Diseases, CHU de Qu\u00e9bec Research Center , Quebec City, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mabrouka","family":"Salem","sequence":"additional","affiliation":[{"name":"Division of Immune and Infectious Diseases, CHU de Qu\u00e9bec Research Center , Quebec City, Quebec,","place":["Canada"]},{"name":"ARThrite Center, Laval University , Quebec City, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7278-2596","authenticated-orcid":false,"given":"Paul R","family":"Fortin","sequence":"additional","affiliation":[{"name":"Division of Immune and Infectious Diseases, CHU de Qu\u00e9bec Research Center , Quebec City, Quebec,","place":["Canada"]},{"name":"ARThrite Center, Laval University , Quebec City, Quebec,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine, Laval University , Quebec City, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2922-1600","authenticated-orcid":false,"given":"Jean","family":"S\u00e9vigny","sequence":"additional","affiliation":[{"name":"Division of Immune and Infectious Diseases, CHU de Qu\u00e9bec Research Center , Quebec City, Quebec,","place":["Canada"]},{"name":"ARThrite Center, Laval University , Quebec City, Quebec,","place":["Canada"]},{"name":"Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University , Quebec City, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9579-2941","authenticated-orcid":false,"given":"Fawzi","family":"Aoudjit","sequence":"additional","affiliation":[{"name":"Division of Immune and Infectious Diseases, CHU de Qu\u00e9bec Research Center , Quebec City, Quebec,","place":["Canada"]},{"name":"ARThrite Center, Laval University , Quebec City, Quebec,","place":["Canada"]},{"name":"Department of Microbiology-Infectiology and Immunology, Faculty of Medicine, Laval University , Quebec City, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,3,1]]},"reference":[{"key":"2025021008572906500_r1","doi-asserted-by":"crossref","first-page":"661","DOI":"10.3389\/fphar.2017.00661","article-title":"Purinergic signalling: therapeutic developments","volume":"8","author":"Burnstock","year":"2017","journal-title":"Front. Pharmacol."},{"key":"2025021008572906500_r2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0074-7696(04)40002-3","article-title":"Cellular distribution and functions of P2 receptor subtypes in different systems","volume":"240","author":"Burnstock","year":"2004","journal-title":"Int. Rev. Cytol."},{"key":"2025021008572906500_r3","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s11302-008-9127-x","article-title":"An evolutionary history of P2X receptors","volume":"5","author":"Fountain","year":"2009","journal-title":"Purinergic Signal."},{"key":"2025021008572906500_r4","doi-asserted-by":"crossref","first-page":"114408","DOI":"10.1016\/j.bcp.2021.114408","article-title":"The P2Y\/P2X divide: how it began","volume":"187","author":"Kennedy","year":"2021","journal-title":"Biochem. Pharmacol."},{"key":"2025021008572906500_r5","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1111\/bph.15005","article-title":"Update of P2Y receptor pharmacology: IUPHAR Review 27","volume":"177","author":"Jacobson","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"2025021008572906500_r6","doi-asserted-by":"crossref","first-page":"627","DOI":"10.3389\/fphar.2020.00627","article-title":"To inhibit or enhance? Is there a benefit to positive allosteric modulation of P2X receptors?","volume":"11","author":"Stokes","year":"2020","journal-title":"Front. Pharmacol."},{"key":"2025021008572906500_r7","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1124\/pr.117.014878","article-title":"The purinergic system as a pharmacological target for the treatment of immune-mediated inflammatory diseases","volume":"71","author":"Antonioli","year":"2019","journal-title":"Pharmacol. Rev."},{"key":"2025021008572906500_r8","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1182\/blood-2010-04-277707","article-title":"Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse","volume":"116","author":"Woehrle","year":"2010","journal-title":"Blood"},{"key":"2025021008572906500_r9","doi-asserted-by":"crossref","first-page":"25936","DOI":"10.1074\/jbc.M114.575308","article-title":"Mitochondria are gate-keepers of T cell function by producing the ATP that drives purinergic signaling","volume":"289","author":"Ledderose","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2025021008572906500_r10","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1093\/infdis\/jiv373","article-title":"Mitochondrial dysfunction, depleted purinergic signaling, and defective T cell vigilance and immune defense","volume":"213","author":"Ledderose","year":"2016","journal-title":"J. Infect. Dis."},{"key":"2025021008572906500_r11","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1096\/fj.08-126458","article-title":"Autocrine regulation of T-cell activation by ATP release and P2X7 receptors","volume":"23","author":"Yip","year":"2009","journal-title":"FASEB J."},{"key":"2025021008572906500_r12","doi-asserted-by":"crossref","first-page":"986789","DOI":"10.1155\/2013\/986789","article-title":"Th17 cells in immunity and autoimmunity","volume":"2013","author":"Bedoya","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"2025021008572906500_r13","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.immuni.2015.12.003","article-title":"Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions","volume":"43","author":"Patel","year":"2015","journal-title":"Immunity"},{"key":"2025021008572906500_r14","doi-asserted-by":"crossref","first-page":"35804","DOI":"10.1038\/srep35804","article-title":"Involvement of P2X7 receptor signaling on regulating the differentiation of Th17 cells and type II collagen-induced arthritis in mice","volume":"6","author":"Fan","year":"2016","journal-title":"Sci. Rep."},{"key":"2025021008572906500_r15","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.4049\/jimmunol.1202045","article-title":"Signaling through purinergic receptors for ATP induces human cutaneous innate and adaptive Th17 responses: implications in the pathogenesis of psoriasis","volume":"190","author":"Killeen","year":"2013","journal-title":"J. Immunol."},{"key":"2025021008572906500_r16","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s11302-017-9569-0","article-title":"The P2X7 receptor is not essential for development of imiquimod-induced psoriasis-like inflammation in mice","volume":"13","author":"Geraghty","year":"2017","journal-title":"Purinergic Signal."},{"key":"2025021008572906500_r17","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1084\/jem.20171976","article-title":"P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus","volume":"216","author":"Faliti","year":"2019","journal-title":"J. Exp. Med."},{"key":"2025021008572906500_r18","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1002\/humu.23218","article-title":"Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis","volume":"38","author":"Sadovnick","year":"2017","journal-title":"Hum. Mutat."},{"key":"2025021008572906500_r19","doi-asserted-by":"crossref","first-page":"e8743","DOI":"10.15252\/emmm.201708743","article-title":"P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis","volume":"10","author":"Zabala","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"2025021008572906500_r20","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.4049\/jimmunol.176.5.3115","article-title":"Exacerbation of experimental autoimmune encephalomyelitis in P2X7R\u2212\/\u2212 mice: evidence for loss of apoptotic activity in lymphocytes","volume":"176","author":"Chen","year":"2006","journal-title":"J. Immunol."},{"key":"2025021008572906500_r21","doi-asserted-by":"crossref","first-page":"72","DOI":"10.4049\/jimmunol.1601549","article-title":"Critical role of P2Y12 receptor in regulation of Th17 differentiation and experimental autoimmune encephalomyelitis pathogenesis","volume":"199","author":"Qin","year":"2017","journal-title":"J. Immunol."},{"key":"2025021008572906500_r22","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.bbi.2016.12.001","article-title":"Knockout of P2Y12 aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells. [Published erratum appears in 2021 Brain Behav. Immun. 91: 801\u2013803.]","volume":"62","author":"Zhang","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"2025021008572906500_r23","doi-asserted-by":"crossref","first-page":"ra12","DOI":"10.1126\/scisignal.2001270","article-title":"ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors","volume":"4","author":"Schenk","year":"2011","journal-title":"Sci. Signal."},{"key":"2025021008572906500_r24","doi-asserted-by":"crossref","first-page":"4198","DOI":"10.4049\/jimmunol.1500437","article-title":"Cooperation between IL-7 receptor and integrin \u03b12\u03b21 (CD49b) drives Th17-mediated bone loss","volume":"195","author":"El Azreq","year":"2015","journal-title":"J. Immunol."},{"key":"2025021008572906500_r25","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.3389\/fimmu.2018.02269","article-title":"Alpha2beta1 integrin (VLA-2) protects activated human effector T cells from methotrexate-induced apoptosis","volume":"9","author":"Abderrazak","year":"2018","journal-title":"Front. Immunol."},{"key":"2025021008572906500_r26","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/ni.1610","article-title":"The differentiation of human TH-17 cells requires transforming growth factor-\u03b2 and induction of the nuclear receptor ROR\u03b3t","volume":"9","author":"Manel","year":"2008","journal-title":"Nat. Immunol."},{"key":"2025021008572906500_r27","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1002\/eji.201040307","article-title":"Alpha2beta1 integrin is the major collagen-binding integrin expressed on human Th17 cells","volume":"40","author":"Boisvert","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"2025021008572906500_r28","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1002\/eji.200526101","article-title":"IL-12 up-regulates T-bet independently of IFN-\u03b3 in human CD4+ T cells","volume":"35","author":"Ylikoski","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"2025021008572906500_r29","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3389\/fphar.2018.00149","article-title":"P2Y6 receptors regulate CXCL10 expression and secretion in mouse intestinal epithelial cells","volume":"9","author":"Salem","year":"2018","journal-title":"Front. Pharmacol."},{"key":"2025021008572906500_r30","doi-asserted-by":"crossref","first-page":"5941","DOI":"10.4049\/jimmunol.1301940","article-title":"\u03b12\u03b21 Integrin regulates Th17 cell activity and its neutralization decreases the severity of collagen-induced arthritis","volume":"191","author":"El Azreq","year":"2013","journal-title":"J. Immunol."},{"key":"2025021008572906500_r31","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1124\/mol.63.6.1407","article-title":"Pharmacological and biophysical properties of the human P2X5 receptor","volume":"63","author":"Bo","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"2025021008572906500_r32","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.neuropharm.2008.06.067","article-title":"ATP-gated P2X cation-channels","volume":"56","author":"Jarvis","year":"2009","journal-title":"Neuropharmacology"},{"key":"2025021008572906500_r33","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000350119","article-title":"Investigation of the inhibitory effects of the benzodiazepine derivative, 5-BDBD on P2X4 purinergic receptors by two complementary methods","volume":"32","author":"Bal\u00e1zs","year":"2013","journal-title":"Cell. Physiol. Biochem."},{"key":"2025021008572906500_r34","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1007\/s002100000312","article-title":"Agonists and antagonists acting at P2X receptors: selectivity profiles and functional implications","volume":"362","author":"Lambrecht","year":"2000","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"2025021008572906500_r35","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/978-1-4939-9717-6_3","article-title":"Agonists and antagonists for purinergic receptors","volume":"2041","author":"M\u00fcller","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"2025021008572906500_r36","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1016\/S0168-9525(02)02684-7","article-title":"Mouse models for rheumatoid arthritis","volume":"18","author":"Lindqvist","year":"2002","journal-title":"Trends Genet."},{"key":"2025021008572906500_r37","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.1172\/JCI120972","article-title":"Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration","volume":"128","author":"Ledderose","year":"2018","journal-title":"J. Clin. Invest."},{"key":"2025021008572906500_r38","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.immuni.2011.12.013","article-title":"Rarity of human T helper 17 cells is due to retinoic acid orphan receptor-dependent mechanisms that limit their expansion","volume":"36","author":"Santarlasci","year":"2012","journal-title":"Immunity"},{"key":"2025021008572906500_r39","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.3389\/fimmu.2018.01159","article-title":"Human P2Y11 expression level affects human P2X7 receptor-mediated cell death","volume":"9","author":"Dreisig","year":"2018","journal-title":"front. immunol."},{"key":"2025021008572906500_r40","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s11302-019-09653-6","article-title":"Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation","volume":"15","author":"Woehrle","year":"2019","journal-title":"Purinergic Signal."},{"key":"2025021008572906500_r41","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3892\/mmr.2015.4622","article-title":"Effect of P2X4R on airway inflammation and airway remodeling in allergic airway challenge in mice","volume":"13","author":"Chen","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"2025021008572906500_r42","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/nature07240","article-title":"ATP drives lamina propria TH17 cell differentiation","volume":"455","author":"Atarashi","year":"2008","journal-title":"Nature"},{"key":"2025021008572906500_r43","doi-asserted-by":"crossref","first-page":"7725","DOI":"10.4049\/jimmunol.174.12.7725","article-title":"Augmentation of cutaneous immune responses by ATP\u03b3S: purinergic agonists define a novel class of immunologic adjuvants","volume":"174","author":"Granstein","year":"2005","journal-title":"J. Immunol."},{"key":"2025021008572906500_r44","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1136\/annrheumdis-2011-143578","article-title":"Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine","volume":"71","author":"Keystone","year":"2012","journal-title":"Ann. Rheum. Dis."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/208\/5\/1115\/61466481\/ji2100550.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/208\/5\/1115\/61466481\/ji2100550.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T08:57:56Z","timestamp":1739177876000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/208\/5\/1115\/7924622"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,1]]},"references-count":44,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,3,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2100550","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,3]]},"published":{"date-parts":[[2022,3,1]]}}}