{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:03:06Z","timestamp":1791518586243,"version":"4.3.4"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,10,24]],"date-time":"2016-10-24T00:00:00Z","timestamp":1477267200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,10,24]],"date-time":"2016-10-24T00:00:00Z","timestamp":1477267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Interleukin (IL)-17 producing T helper (Th17) cells are major effector cells in the pathogenesis of rheumatoid arthritis (RA). The P2X7 receptor (P2X7R) has emerged as a potential site in the regulation of inflammation in RA but little is known of its functional role on the differentiation of Th17 cells. This study investigates the<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>effects of P2X7R on Th17 cell differentiation during type II collagen (CII) induced experimental arthritis model. In CII-treated dendritic cells (DCs) and DC\/CD4<jats:sup>+<\/jats:sup>T coculture system, pretreatment with pharmacological antagonists of P2X7R (Suramin and A-438079) caused strong inhibition of production of Th17-promoting cytokines (IL-1\u03b2, TGF-\u03b21, IL-23p19 and IL-6). Exposure to CII induced the elevation of mRNAs encoding retinoic acid receptor-related orphan receptor \u03b1 and \u03b3t, which were abolished by pretreatment with P2X7R antagonists. Furthermore, blocking P2X7R signaling abolished the CII-mediated increase in IL-17A. Blockade of P2X7R remarkably inhibited hind paw swelling and ameliorated pathological changes in ankle joint of the collagen-induced arthritis mice. Thus, we demonstrated a novel function for P2X7R signaling in regulating CII-induced differentiation of Th17 cells. P2X7R signaling facilitates the development of the sophisticated network of DC-derived cytokines that favors a Th17 phenotype.<\/jats:p>","DOI":"10.1038\/srep35804","type":"journal-article","created":{"date-parts":[[2016,10,24]],"date-time":"2016-10-24T10:40:59Z","timestamp":1477305659000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Involvement of P2X7 receptor signaling on regulating the differentiation of Th17 cells and type II collagen-induced arthritis in mice"],"prefix":"10.1038","volume":"6","author":[{"given":"Zhi-Dan","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Yuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Hong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Hui","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Guo","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,10,24]]},"reference":[{"key":"BFsrep35804_CR1","doi-asserted-by":"publisher","first-page":"S39","DOI":"10.1097\/01.rhu.0000166673.34461.33","volume":"11","author":"GS Firestein","year":"2005","unstructured":"Firestein, G. S. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J. Clin. Rheumatol. 11, S39\u2013S44 (2005).","journal-title":"J. Clin. Rheumatol."},{"key":"BFsrep35804_CR2","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/S0889-857X(05)70201-5","volume":"27","author":"SE Gabriel","year":"2001","unstructured":"Gabriel, S. E. The epidemiology of rheumatoid arthritis. Rheum. Dis. Clin. North. Am. 27, 269\u2013281 (2001).","journal-title":"Rheum. Dis. Clin. North. Am."},{"key":"BFsrep35804_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/01.wnq.0000203278.74526.79","volume":"16","author":"JS Silber","year":"2006","unstructured":"Silber, J. S., Verma, R. B. & Greenberg, A. S. Rheumatoid arthritis of the cervical spine. Neurosurg. Q. 16, 1\u20138 (2006).","journal-title":"Neurosurg. Q."},{"key":"BFsrep35804_CR4","first-page":"871","volume":"30","author":"M Fukase","year":"1980","unstructured":"Fukase, M., Koizumi, F. & Wakaki, K. Histopathologic analysis of 16 subcutaneous rheumatoid nodules. Acta. Pathol. Jpn. 30, 871\u2013882 (1980).","journal-title":"Acta. Pathol. Jpn."},{"key":"BFsrep35804_CR5","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.semarthrit.2015.06.010","volume":"45","author":"H Radner","year":"2015","unstructured":"Radner, H. et al. Development of a multimorbidity index: Impact on quality of life using a rheumatoid arthritis cohort. Semin. Arthritis. Rheum. 45, 167\u2013173 (2015).","journal-title":"Semin. Arthritis. Rheum."},{"key":"BFsrep35804_CR6","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1111\/jep.12399","volume":"21","author":"L Hromadkova","year":"2015","unstructured":"Hromadkova, L., Soukup, T. & Vlcek, J. Quality of life and drug compliance: their interrelationship in rheumatic patients. J. Eval. Clin. Pract. 21, 919\u2013924 (2015).","journal-title":"J. Eval. Clin. Pract."},{"key":"BFsrep35804_CR7","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1016\/j.clinthera.2015.07.001","volume":"37","author":"MY Lee","year":"2015","unstructured":"Lee, M. Y. et al. Cost-effectiveness of tofacitinib in the treatment of moderate to severe rheumatoid arthritis in South Korea. Clin. Ther. 37, 1662\u20131676 (2015).","journal-title":"Clin. Ther."},{"key":"BFsrep35804_CR8","doi-asserted-by":"publisher","first-page":"516","DOI":"10.5312\/wjo.v5.i4.516","volume":"5","author":"L Magyari","year":"2014","unstructured":"Magyari, L. et al. Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World. J. Orthop. 5, 516\u2013536 (2014).","journal-title":"World. J. Orthop."},{"key":"BFsrep35804_CR9","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1136\/annrheumdis-2013-204573","volume":"73","author":"JS Smolen","year":"2014","unstructured":"Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann. Rheum. Dis. 73, 492\u2013509 (2014).","journal-title":"Ann. Rheum. Dis."},{"key":"BFsrep35804_CR10","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.jbspin.2004.12.012","volume":"72","author":"C Fournier","year":"2005","unstructured":"Fournier, C. Where do T cells stand in rheumatoid arthritis? Joint Bone Spine 72, 527\u2013532 (2005).","journal-title":"Joint Bone Spine"},{"key":"BFsrep35804_CR11","doi-asserted-by":"crossref","first-page":"751793","DOI":"10.1155\/2015\/751793","volume":"2015","author":"A Alunno","year":"2015","unstructured":"Alunno, A. et al. Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. Mediators Inflamm. 2015, 751793 (2015).","journal-title":"Mediators Inflamm."},{"key":"BFsrep35804_CR12","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.cyto.2015.02.002","volume":"74","author":"SM Paulissen","year":"2015","unstructured":"Paulissen, S. M., van Hamburg, J. P., Dankers, W. & Lubberts, E. The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis. Cytokine 74, 43\u201353 (2015).","journal-title":"Cytokine"},{"key":"BFsrep35804_CR13","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1186\/ar113","volume":"2","author":"T Pap","year":"2000","unstructured":"Pap, T., M\u00fcller-Ladner, U., Gay, R. E. & Gay, S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis. Res. 2, 361\u2013367 (2000).","journal-title":"Arthritis. Res."},{"key":"BFsrep35804_CR14","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1093\/rheumatology\/ket414","volume":"53","author":"DE Furst","year":"2014","unstructured":"Furst, D. E. & Emery, P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatology (Oxford) 53, 1560\u20131569 (2014).","journal-title":"Rheumatology (Oxford)"},{"key":"BFsrep35804_CR15","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1056\/NEJMra1004965","volume":"365","author":"IB McInnes","year":"2011","unstructured":"McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205\u20132219 (2011).","journal-title":"N. Engl. J. Med."},{"key":"BFsrep35804_CR16","first-page":"413","volume":"11","author":"G Ferraccioli","year":"2011","unstructured":"Ferraccioli, G. & Zizzo, G. The potential role of Th17 in mediating the transition from acute to chronic autoimmune inflammation: rheumatoid arthritis as a model. Discov. Med. 11, 413\u2013424 (2011).","journal-title":"Discov. Med."},{"key":"BFsrep35804_CR17","doi-asserted-by":"publisher","first-page":"5625","DOI":"10.4049\/jimmunol.180.8.5625","volume":"180","author":"PF Cheung","year":"2008","unstructured":"Cheung, P. F., Wong, C. K. & Lam, C. W. Molecular mechanisms of cytokine and chemokine release from eosinophils activated by IL-17A, IL-17F, and IL-23: implication for Th17 lymphocytes-mediated allergic inflammation. J. Immunol. 180, 5625\u20135635 (2008).","journal-title":"J. Immunol."},{"key":"BFsrep35804_CR18","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.4049\/jimmunol.170.5.2655","volume":"170","author":"E Lubberts","year":"2003","unstructured":"Lubberts, E. et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand\/osteoprotegerin balance. J. Immunol. 170, 2655\u20132662 (2003).","journal-title":"J. Immunol."},{"key":"BFsrep35804_CR19","doi-asserted-by":"publisher","first-page":"5346","DOI":"10.1038\/onc.2010.292","volume":"29","author":"J Stagg","year":"2010","unstructured":"Stagg, J. & Smyth M. J. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29, 5346\u20135358 (2010).","journal-title":"Oncogene"},{"key":"BFsrep35804_CR20","doi-asserted-by":"publisher","first-page":"2611","DOI":"10.4049\/jimmunol.1000436","volume":"185","author":"G Lopez-Castejon","year":"2010","unstructured":"Lopez-Castejon, G. et al. P2X(7) receptor-mediated release of cathepsins from macrophages is a cytokine-independent mechanism potentially involved in joint diseases. J. Immunol. 185, 2611\u20132619 (2010).","journal-title":"J. Immunol."},{"key":"BFsrep35804_CR21","doi-asserted-by":"publisher","first-page":"408242","DOI":"10.1155\/2012\/408242","volume":"2012","author":"A Baroja-Mazo","year":"2012","unstructured":"Baroja-Mazo, A. & Pelegr\u00edn, P. Modulating P2X7 receptor signaling during rheumatoid arthritis: new therapeutic approaches for bisphosphonates. J. Osteoporos. 2012, 408242 (2012).","journal-title":"J. Osteoporos."},{"key":"BFsrep35804_CR22","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1002\/eji.201242741","volume":"42","author":"F Sallusto","year":"2012","unstructured":"Sallusto, F., Zielinski, C. E. & Lanzavecchia, A. Human Th17 subsets. Eur. J. Immunol. 42, 2215\u20132220 (2012).","journal-title":"Eur. J. Immunol."},{"key":"BFsrep35804_CR23","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/ni1496","volume":"8","author":"EV Acosta-Rodriguez","year":"2007","unstructured":"Acosta-Rodriguez, E. V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 8, 942\u2013949 (2007).","journal-title":"Nat. Immunol."},{"key":"BFsrep35804_CR24","doi-asserted-by":"publisher","first-page":"e27289","DOI":"10.1371\/journal.pone.0027289","volume":"6","author":"L Wang","year":"2011","unstructured":"Wang, L. et al. Up-regulation of Th17 cells may underlie inhibition of Treg development caused by immunization with activated syngeneic T cells. PLoS One 6, e27289 (2011).","journal-title":"PLoS One"},{"key":"BFsrep35804_CR25","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/sj.cr.7310083","volume":"16","author":"L Wang","year":"2006","unstructured":"Wang, L. et al. Immunization with autologous T cells enhances in vivo anti-tumor immune responses accompanied by up-regulation of GADD45beta. Cell Res. 16, 702\u2013712 (2006).","journal-title":"Cell Res."},{"key":"BFsrep35804_CR26","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1038\/gt.2011.145","volume":"19","author":"ZD Fan","year":"2012","unstructured":"Fan, Z. D. et al. Artificial microRNA interference targeting AT(1a) receptors in paraventricular nucleus attenuates hypertension in rats. Gene Ther. 19, 810\u2013817 (2012).","journal-title":"Gene Ther."},{"key":"BFsrep35804_CR27","doi-asserted-by":"publisher","first-page":"e50366","DOI":"10.1371\/journal.pone.0050366","volume":"7","author":"HA Elshabrawy","year":"2012","unstructured":"Elshabrawy, H. A., Coughlin, M. M., Baker, S. C. & Prabhakar, B. S. Human monoclonal antibodies against highly conserved HR1 and HR2 domains of the SARS-CoV spike protein are more broadly neutralizing. PLoS One 7, e50366 (2012).","journal-title":"PLoS One"},{"key":"BFsrep35804_CR28","doi-asserted-by":"publisher","first-page":"4353","DOI":"10.1128\/JVI.03050-13","volume":"88","author":"HA Elshabrawy","year":"2014","unstructured":"Elshabrawy, H. A. et al. Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay. J. Virol. 88, 4353\u20134365 (2014).","journal-title":"J. Virol."},{"key":"BFsrep35804_CR29","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1007\/s12272-015-0557-z","volume":"38","author":"EG Jung","year":"2015","unstructured":"Jung, E. G. et al. Anti-inflammatory activity of sappanchalcone isolated from Caesalpinia sappan L. in a collagen-induced arthritismouse model. Arch. Pharm. Res. 38, 973\u2013983 (2015).","journal-title":"Arch. Pharm. Res."},{"key":"BFsrep35804_CR30","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1136\/ard.2011.153056","volume":"71","author":"G Pongratz","year":"2012","unstructured":"Pongratz, G., Melzer, M. & Straub, R. H. The sympathetic nervous system stimulates anti-inflammatory B cells in collagen-type II-induced arthritis. Ann. Rheum. Dis. 71, 432\u2013439 (2012).","journal-title":"Ann. Rheum. Dis."},{"key":"BFsrep35804_CR31","doi-asserted-by":"publisher","first-page":"993","DOI":"10.3892\/ol.2013.1518","volume":"6","author":"J Hu","year":"2013","unstructured":"Hu, J. et al. U87MG glioma cells overexpressing IL-17 acclerate early-stage growth in vivo and cause a higher level of CD31 mRNA expression in tumor tissues. Oncol. Lett. 6, 993\u2013999 (2013).","journal-title":"Oncol. Lett."},{"key":"BFsrep35804_CR32","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1002\/art.39544","volume":"68","author":"SJ Kim","year":"2016","unstructured":"Kim, S. J. et al. Identification of a novel Toll-like receptor 7 endogenous ligand in rheumatoid arthritis synovial fluid that can provoke arthritic joint inflammation. Arthritis Rheumatol. 68, 1099\u20131110 (2016).","journal-title":"Arthritis Rheumatol."},{"key":"BFsrep35804_CR33","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.intimp.2012.07.001","volume":"14","author":"R Li","year":"2012","unstructured":"Li, R. et al. Therapeutic effect of 7,3\u2032-dimethoxy hesperetin on adjuvant arthritis in rats through inhibiting JAK2-STAT3 signal pathway. Int. Immunopharmacol. 14, 157\u2013163 (2012).","journal-title":"Int. Immunopharmacol."},{"key":"BFsrep35804_CR34","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/nm1617","volume":"13","author":"M Idzko","year":"2007","unstructured":"Idzko, M. et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat. Med. 13, 913\u2013919 (2007).","journal-title":"Nat. Med."},{"key":"BFsrep35804_CR35","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1111\/j.1399-0039.2011.01780.x","volume":"78","author":"JS Wiley","year":"2011","unstructured":"Wiley, J. S., Sluyter, R., Gu, B. J., Stokes, L. & Fuller, S. J. The human P2X7 receptor and its role in innate immunity. Tissue Antigens 78, 321\u2013332 (2011).","journal-title":"Tissue Antigens"},{"key":"BFsrep35804_CR36","first-page":"716","volume":"18","author":"LM Ryan","year":"1991","unstructured":"Ryan, L. M., Rachow, J. W. & McCarty, D. J. Synovial fluid ATP: a potential substrate for the production of inorganic pyrophosphate. J. Rheumatol. 18, 716\u2013720 (1991).","journal-title":"J. Rheumatol."},{"key":"BFsrep35804_CR37","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1016\/j.humimm.2010.05.008","volume":"71","author":"L Portales-Cervantes","year":"2010","unstructured":"Portales-Cervantes, L. et al. Expression and function of the P2X(7) purinergic receptor in patients with systemic lupus erythematosus andrheumatoid arthritis. Hum. Immunol. 71, 818\u2013825 (2010).","journal-title":"Hum. Immunol."},{"key":"BFsrep35804_CR38","doi-asserted-by":"publisher","first-page":"6436","DOI":"10.4049\/jimmunol.168.12.6436","volume":"168","author":"JM Labasi","year":"2002","unstructured":"Labasi, J. M. et al. Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J. Immunol. 168, 6436\u20136445 (2002).","journal-title":"J. Immunol."},{"key":"BFsrep35804_CR39","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1523\/JNEUROSCI.3902-05.2006","volume":"26","author":"SO Suadicani","year":"2006","unstructured":"Suadicani, S. O., Brosnan, C. F. & Scemes, E. P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J. Neurosci. 26, 1378\u20131385 (2006).","journal-title":"J. Neurosci."},{"key":"BFsrep35804_CR40","doi-asserted-by":"publisher","first-page":"41","DOI":"10.3389\/fendo.2012.00041","volume":"3","author":"A Brandao-Burch","year":"2012","unstructured":"Brandao-Burch, A., Key, M. L., Patel, J. J., Arnett, T. R. & Orriss, I. R. The P2X7 receptor is an important regulator of extracellular ATP levels. Front Endocrinol (Lausanne) 3, 41 (2012).","journal-title":"Front Endocrinol (Lausanne)"},{"key":"BFsrep35804_CR41","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1096\/fj.10-169854","volume":"25","author":"P Pellegatti","year":"2011","unstructured":"Pellegatti, P., Falzoni, S., Donvito, G., Lemaire, I. & Di Virgilio, F. P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration. FASEB. J. 25, 1264\u20131274 (2011).","journal-title":"FASEB. J."},{"key":"BFsrep35804_CR42","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1038\/nprot.2007.173","volume":"2","author":"DD Brand","year":"2007","unstructured":"Brand, D. D., Latham, K. A. & Rosloniec, E. F. Collagen-induced arthritis. Nat. Protoc. 2, 1269\u20131275 (2007).","journal-title":"Nat. Protoc."},{"key":"BFsrep35804_CR43","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1002\/1529-0131(199910)42:10<2085::AID-ANR8>3.0.CO;2-Z","volume":"42","author":"HY Kim","year":"1999","unstructured":"Kim, H. Y. et al. Enhanced T cell proliferative response to type II collagen and synthetic peptide CII (255\u2013274) in patients with rheumatoid arthritis. Arthritis Rheum. 42, 2085\u20132093 (1999).","journal-title":"Arthritis Rheum."},{"key":"BFsrep35804_CR44","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1073\/pnas.86.2.636","volume":"86","author":"M Londei","year":"1989","unstructured":"Londei, M. et al. Persistence of collagen type II-specific T-cell clones in the synovial membrane of a patient with rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 86, 636\u2013640 (1989).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep35804_CR45","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1002\/art.1780331006","volume":"33","author":"Kv Terato","year":"1990","unstructured":"Terato, K. v. Specificity of antibodies to type II collagen in rheumatoid arthritis. Arthritis Rheum. 33, 1493\u20131500 (1990).","journal-title":"Arthritis Rheum."},{"key":"BFsrep35804_CR46","doi-asserted-by":"publisher","first-page":"2951","DOI":"10.1096\/fj.12-205765","volume":"26","author":"M Barber\u00e0-Cremades","year":"2012","unstructured":"Barber\u00e0-Cremades, M. et al. P2X7 receptor-stimulation causes fever via PGE2 and IL-1\u03b2 release. FASEB. J. 26, 2951\u20132962 (2012).","journal-title":"FASEB. J."},{"key":"BFsrep35804_CR47","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1517\/13543784.2011.578068","volume":"20","author":"N Arulkumaran","year":"2011","unstructured":"Arulkumaran, N., Unwin, R. J. & Tam, F. W. A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases. Expert Opin. Investig. Drugs 20, 897\u2013915 (2011).","journal-title":"Expert Opin. Investig. Drugs"},{"key":"BFsrep35804_CR48","doi-asserted-by":"publisher","first-page":"41","DOI":"10.3389\/fendo.2012.00041","volume":"3","author":"A Brandao-Burch","year":"2012","unstructured":"Brandao-Burch, A., Key, M. L., Patel, J. J., Arnett, T. R. & Orriss, I. R. The P2X7 receptor is an important regulator of extracellular ATP levels. Front Endocrinol. 3, 41 (2012).","journal-title":"Front Endocrinol."},{"key":"BFsrep35804_CR49","first-page":"962","volume":"275","author":"E Schulze-Lohoff","year":"1998","unstructured":"Schulze-Lohoff, E. et al. Extracellular ATP causes apoptosis and necrosis of cultured mesangial cells via P2Z\/P2X7 receptors. Am. J. Physiol. 275, 962\u2013971 (1998).","journal-title":"Am. J. Physiol."},{"key":"BFsrep35804_CR50","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1161\/CIRCULATIONAHA.112.123653","volume":"127","author":"A Vergani","year":"2013","unstructured":"Vergani, A. et al. Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation 127, 463\u2013475 (2013).","journal-title":"Circulation"},{"key":"BFsrep35804_CR51","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1111\/ajt.12741","volume":"14","author":"JA Sullivan","year":"2014","unstructured":"Sullivan, J. A. et al. Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses. Am. J. Transplant. 14, 1512\u20131522 (2014).","journal-title":"Am. J. Transplant."},{"key":"BFsrep35804_CR52","doi-asserted-by":"publisher","first-page":"4324","DOI":"10.4049\/jimmunol.1202045","volume":"190","author":"ME Killeen","year":"2013","unstructured":"Killeen, M. E., Ferris, L., Kupetsky, E. A., Jr. Falo, L. & Mathers, A. R. Signaling through purinergic receptors for ATP induces human cutaneous innate and adaptive Th17 responses: implications in the pathogenesis of psoriasis. J. Immunol. 190, 4324\u20134336 (2013).","journal-title":"J. Immunol."},{"key":"BFsrep35804_CR53","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1002\/glia.22628","volume":"62","author":"CH Shieh","year":"2014","unstructured":"Shieh, C. H., Heinrich, A., Serchov, T., van Calker, D. & Biber, K. P2X7-dependent, but differentially regulated release of IL-6, CCL2, and TNF-\u03b1 in cultured mouse microglia. Glia 62, 592\u2013607 (2014).","journal-title":"Glia"},{"key":"BFsrep35804_CR54","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.ijpara.2010.10.001","volume":"41","author":"CM Miller","year":"2011","unstructured":"Miller, C. M. et al. Dysregulation of the inflammatory response to the parasite, Toxoplasma gondii, in P2X7 receptor-deficient mice. Int. J. Parasitol. 41, 301\u2013308 (2011).","journal-title":"Int. J. Parasitol."},{"key":"BFsrep35804_CR55","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.rinim.2013.06.001","volume":"3","author":"N Fazal","year":"2013","unstructured":"Fazal, N. OX62+OX6+OX35+ rat dendritic cells are unable to prime CD4+ T cells for an effective immune response following acute burn injury. Results Immunol. 3, 64\u201372 (2013).","journal-title":"Results Immunol."},{"key":"BFsrep35804_CR56","doi-asserted-by":"publisher","first-page":"408242","DOI":"10.1155\/2012\/408242","volume":"2012","author":"A Baroja-Mazo","year":"2012","unstructured":"Baroja-Mazo, A. & Pelegr\u00edn, P. Modulating P2X7 receptor signaling during rheumatoid arthritis: new therapeutic approaches for bisphosphonates. J. Osteoporos. 2012, 408242 (2012).","journal-title":"J. Osteoporos."},{"key":"BFsrep35804_CR57","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.intimp.2015.05.023","volume":"28","author":"J Yu","year":"2015","unstructured":"Yu, J. et al. Paeoniflorin down-regulates ATP-induced inflammatory cytokine production and P2X7R expression on peripheral blood mononuclear cells from patients with primary Sj\u00f6gren\u2019s syndrome. Int. Immunopharmacol. 28, 115\u2013120 (2015).","journal-title":"Int. Immunopharmacol."},{"key":"BFsrep35804_CR58","doi-asserted-by":"publisher","first-page":"3659","DOI":"10.1091\/mbc.e05-03-0222","volume":"16","author":"P Pellegatti","year":"2005","unstructured":"Pellegatti, P., Falzoni, S., Pinton, P., Rizzuto, R. & Di Virgilio, F. A novel recombinant plasma membrane-targeted luciferase reveals a new pathway for ATP secretion. Mol. Biol. Cell 16, 3659\u20133665 (2005).","journal-title":"Mol. Biol. Cell"},{"key":"BFsrep35804_CR59","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1196\/annals.1378.027","volume":"1090","author":"EM Schneider","year":"2006","unstructured":"Schneider, E. M., Vorlaender, K., Ma, X., Du, W. & Weiss, M. Role of ATP in trauma-associated cytokine release and apoptosis by P2X7 ion channel stimulation. Ann. N. Y. Acad. Sci. 1090, 245\u2013252 (2006).","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"BFsrep35804_CR60","doi-asserted-by":"publisher","first-page":"10555","DOI":"10.1038\/ncomms10555","volume":"7","author":"M Karmakar","year":"2016","unstructured":"Karmakar, M., Katsnelson, M. A., Dubyak, G. R. & Pearlman, E. Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1\u03b2 secretion in response to ATP. Nat. Commun. 7, 10555 (2016).","journal-title":"Nat. Commun."},{"key":"BFsrep35804_CR61","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/S0898-6568(03)00112-8","volume":"15","author":"CM Wang","year":"2003","unstructured":"Wang, C. M., Chang, Y. Y. & Sun, S. H. Activation of P2X7 purinoceptor-stimulated TGF-beta 1 mRNA expression involves PKC\/MAPK signallingpathway in a rat brain-derived type-2 astrocyte cell line, RBA-2. Cell Signal. 15, 1129\u20131137 (2003).","journal-title":"Cell Signal."},{"key":"BFsrep35804_CR62","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.brainresbull.2013.02.002","volume":"94","author":"H Xu","year":"2013","unstructured":"Xu, H. et al. High fatty acids modulate P2X(7) expression and IL-6 release via the p38 MAPK pathway in PC12 cells. Brain Res. Bull. 94, 63\u201370 (2013).","journal-title":"Brain Res. Bull."},{"key":"BFsrep35804_CR63","doi-asserted-by":"publisher","first-page":"e82580","DOI":"10.1371\/journal.pone.0082580","volume":"8","author":"PM Schlegel","year":"2013","unstructured":"Schlegel, P. M., Steiert, I., K\u00f6tter, I. & M\u00fcller, C. A. B cells contribute to heterogeneity of IL-17 producing cells in rheumatoid arthritis and healthy controls. PLoS One 8, e82580 (2013).","journal-title":"PLoS One"},{"key":"BFsrep35804_CR64","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1038\/ni.2569","volume":"14","author":"DA Bermejo","year":"2013","unstructured":"Bermejo, D. A. et al. Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors ROR\u03b3t and Ahr that leads to IL-17 production by activated B cells. Nat. Immunol. 14, 514\u2013522 (2013).","journal-title":"Nat. Immunol."},{"key":"BFsrep35804_CR65","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.ceca.2015.01.010","volume":"57","author":"A Pippel","year":"2015","unstructured":"Pippel, A., Be\u00dfler, B., Klapperst\u00fcck, M. & Markwardt, F. Inhibition of antigen receptor-dependent Ca(2+) signals and NF-AT activation by P2X7 receptors in human B lymphocytes. Cell Calcium 57, 275\u2013289 (2015).","journal-title":"Cell Calcium"},{"key":"BFsrep35804_CR66","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1089\/jir.2014.0149","volume":"35","author":"P Bhattacharya","year":"2015","unstructured":"Bhattacharya, P. et al. Dual role of GM-CSF as a pro-Inflammatory and a regulatory cytokine: implications for immune therapy. J. Interferon Cytokine Res. 35, 585\u2013599 (2015).","journal-title":"J. Interferon Cytokine Res."},{"key":"BFsrep35804_CR67","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.cyto.2015.05.030","volume":"75","author":"P Bhattacharya","year":"2015","unstructured":"Bhattacharya, P. et al. GM-CSF: An immune modulatory cytokine that can suppress autoimmunity. Cytokine 75, 261\u2013271 (2015).","journal-title":"Cytokine"},{"key":"BFsrep35804_CR68","doi-asserted-by":"publisher","first-page":"7006","DOI":"10.4049\/jimmunol.174.11.7006","volume":"174","author":"E Gangi","year":"2005","unstructured":"Gangi, E., Vasu, C., Cheatem, D. & Prabhakar, B. S. IL-10-producing CD4+CD25+ regulatory T cells play a critical role in granulocyte-macrophage colony-stimulating factor-induced suppression of experimental autoimmune thyroiditis. J. Immunol. 174, 7006\u20137013 (2005).","journal-title":"J. Immunol."},{"key":"BFsrep35804_CR69","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1097\/MIB.0b013e318281f506","volume":"19","author":"G Gathungu","year":"2013","unstructured":"Gathungu, G. et al. Granulocyte-macrophage colony-stimulating factor autoantibodies: a marker of aggressive Crohn\u2019s disease. Inflamm. Bowel Dis. 19, 1671\u20131680 (2013).","journal-title":"Inflamm. Bowel Dis."},{"key":"BFsrep35804_CR70","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1002\/mus.23488","volume":"46","author":"J Rowin","year":"2012","unstructured":"Rowin, J. et al. Granulocyte macrophage colony-stimulating factor treatment of a patient in myasthenic crisis: effects on regulatory T cells. Muscle Nerve 46, 449\u2013453 (2012).","journal-title":"Muscle Nerve"},{"key":"BFsrep35804_CR71","doi-asserted-by":"publisher","first-page":"2512","DOI":"10.1111\/jcmm.12376","volume":"18","author":"SM Farooq","year":"2014","unstructured":"Farooq, S. M., Kumar A. & Ashour, H. M. Eye-mediated immune tolerance to Type II collagen in arthritis-prone strains of mice. J. Cell Mol. Med. 18, 2512\u20132518 (2014).","journal-title":"J. Cell Mol. Med."},{"key":"BFsrep35804_CR72","doi-asserted-by":"publisher","first-page":"e48635","DOI":"10.1371\/journal.pone.0048635","volume":"7","author":"SM Farooq","year":"2012","unstructured":"Farooq, S. M. & Ashour, H. M. Type II collagen induces peripheral tolerance in BALB\/c mice via the generation of CD8+ T regulatory cells. PLoS One 7, e48635 (2012).","journal-title":"PLoS One"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep35804.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep35804","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep35804.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T20:24:35Z","timestamp":1749673475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep35804"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,24]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,21]]}},"alternative-id":["BFsrep35804"],"URL":"https:\/\/doi.org\/10.1038\/srep35804","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,24]]},"assertion":[{"value":"17 May 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 October 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"35804"}}