{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T04:30:32Z","timestamp":1773721832095,"version":"3.50.1"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:00:00Z","timestamp":1619395200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:00:00Z","timestamp":1619395200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["20K08777"],"award-info":[{"award-number":["20K08777"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gout is an autoinflammatory disease driven by interleukin-1 (IL-1) induction in response to uric acid crystals. IL-1\u03b2 production is dependent on inflammasome activation, which requires a priming signal, followed by an activating signal. The cold-inducible RNA-binding protein (CIRP) has been recently identified as a damage-associated molecular pattern (DAMP). In this study, we evaluated the roles of CIRP in monosodium urate (MSU)-mediated IL-1\u03b2 secretion using human neutrophils.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human neutrophils were stimulated by MSU in the presence or absence of CIRP priming to determine NLRP3 inflammasome activation and subsequent caspase-1 activation and IL-1\u03b2 production. Cellular supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) to determine the presence of IL-1\u03b2 or caspase-1 (p20). The cellular supernatants and lysates were also analyzed by immunoblotting using anti-cleaved IL-1\u03b2 or anti-cleaved caspase-1 antibodies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Neither CIRP nor MSU stimulation alone induced sufficient IL-1\u03b2 secretion from neutrophils. However, MSU stimulation induced IL-1\u03b2 secretion from CIRP-primed neutrophils in a dose-dependent manner. This MSU-induced IL-1\u03b2 secretion from CIRP-primed neutrophils was accompanied by the induction of cleaved IL-1\u03b2 (p17), which was inhibited by the pretreatment of MCC950, a specific inhibitor for NLRP3. Furthermore, cleaved caspase-1 was induced in the cellular lysates of CIRP\/MSU-treated neutrophils. Additionally, CIRP stimulation induced the protein expression of pro-IL-1\u03b2 in neutrophils.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data indicate that CIRP, an endogenous stress molecule, triggers uric acid-induced mature IL-1\u03b2 induction as a priming stimulus for NLRP3 inflammasome in human neutrophils. We propose that CIRP acts as an important proinflammatory stimulant that primes and activates inflammasome and pro-IL-1\u03b2 processing in response to uric acid in innate immune cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-021-02508-9","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:02:44Z","timestamp":1619395364000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cold-inducible RNA-binding protein (CIRP) potentiates uric acid-induced IL-1\u03b2 production"],"prefix":"10.1186","volume":"23","author":[{"given":"Yuya","family":"Fujita","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Yago","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruki","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Asano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Matsuoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jumpei","family":"Temmoku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuzo","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makiko","family":"Yashiro-Furuya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiji","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Kawakami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyoshi","family":"Migita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,26]]},"reference":[{"issue":"3","key":"2508_CR1","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1097\/00002281-200105000-00015","volume":"13","author":"CA Agudelo","year":"2001","unstructured":"Agudelo CA, Wise CM. Gout: diagnosis, pathogenesis, and clinical manifestations. Curr Opin Rheumatol. 2001;13(3):234\u20139. https:\/\/doi.org\/10.1097\/00002281-200105000-00015.","journal-title":"Curr Opin Rheumatol"},{"issue":"6","key":"2508_CR2","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1016\/j.jaci.2009.11.016","volume":"124","author":"R Goldbach-Mansky","year":"2009","unstructured":"Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124(6):1141\u20139; quiz 1150-1141. https:\/\/doi.org\/10.1016\/j.jaci.2009.11.016.","journal-title":"J Allergy Clin Immunol"},{"issue":"1","key":"2508_CR3","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.coi.2009.01.006","volume":"21","author":"JH Pedra","year":"2009","unstructured":"Pedra JH, Cassel SL, Sutterwala FS. Sensing pathogens and danger signals by the inflammasome. Curr Opin Immunol. 2009;21(1):10\u20136. https:\/\/doi.org\/10.1016\/j.coi.2009.01.006.","journal-title":"Curr Opin Immunol"},{"issue":"7081","key":"2508_CR4","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/nature04516","volume":"440","author":"F Martinon","year":"2006","unstructured":"Martinon F, P\u00e9trilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237\u2013241.3. https:\/\/doi.org\/10.1038\/nature04516.","journal-title":"Nature."},{"issue":"1","key":"2508_CR5","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1111\/j.1600-065X.2011.01037.x","volume":"243","author":"MF Fontana","year":"2011","unstructured":"Fontana MF, Vance RE. Two signal models in innate immunity. Immunol Rev. 2011;243(1):26\u201339. https:\/\/doi.org\/10.1111\/j.1600-065X.2011.01037.x.","journal-title":"Immunol Rev"},{"issue":"2","key":"2508_CR6","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.molmed.2016.12.007","volume":"23","author":"MN Patel","year":"2017","unstructured":"Patel MN, Carroll RG, Galv\u00e1n-Pe\u00f1a S, Mills EL, Olden R, Triantafilou M, et al. Inflammasome priming in sterile inflammatory disease. Trends Mol Med. 2017;23(2):165\u201380. https:\/\/doi.org\/10.1016\/j.molmed.2016.12.007.","journal-title":"Trends Mol Med"},{"issue":"10","key":"2508_CR7","doi-asserted-by":"publisher","first-page":"4162","DOI":"10.1096\/fj.14-267393","volume":"29","author":"T Gicquel","year":"2015","unstructured":"Gicquel T, Robert S, Loyer P, Victoni T, Bodin A, Ribault C, et al. IL-1beta production is dependent on the activation of purinergic receptors and NLRP3 pathway in human macrophages. FASEB J. 2015;29(10):4162\u201373. https:\/\/doi.org\/10.1096\/fj.14-267393.","journal-title":"FASEB J"},{"key":"2508_CR8","doi-asserted-by":"publisher","first-page":"70","DOI":"10.3389\/fimmu.2019.00070","volume":"10","author":"BM Alberts","year":"2019","unstructured":"Alberts BM, Bruce C, Basnayake K, Ghezzi P, Davies KA, Mullen LM. Secretion of IL-1beta from monocytes in gout is redox independent. Front Immunol. 2019;10:70. https:\/\/doi.org\/10.3389\/fimmu.2019.00070.","journal-title":"Front Immunol"},{"issue":"8","key":"2508_CR9","doi-asserted-by":"publisher","first-page":"3995","DOI":"10.4049\/jimmunol.1301681","volume":"191","author":"T Fernandes-Alnemri","year":"2013","unstructured":"Fernandes-Alnemri T, Kang S, Anderson C, Sagara J, Fitzgerald KA, Alnemri ES. TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J Immunol. 2013;191(8):3995\u20139. https:\/\/doi.org\/10.4049\/jimmunol.1301681.","journal-title":"J Immunol"},{"key":"2508_CR10","doi-asserted-by":"publisher","first-page":"2536","DOI":"10.3389\/fimmu.2019.02536","volume":"10","author":"NL Denning","year":"2019","unstructured":"Denning NL, Aziz M, Gurien SD, Wang P. DAMPs and NETs in sepsis. Front Immunol. 2019;10:2536. https:\/\/doi.org\/10.3389\/fimmu.2019.02536.","journal-title":"Front Immunol"},{"issue":"2","key":"2508_CR11","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1097\/BOR.0000000000000143","volume":"27","author":"A Dumusc","year":"2015","unstructured":"Dumusc A, So A. Interleukin-1 as a therapeutic target in gout. Curr Opin Rheumatol. 2015;27(2):156\u201363. https:\/\/doi.org\/10.1097\/BOR.0000000000000143.","journal-title":"Curr Opin Rheumatol"},{"key":"2508_CR12","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.3389\/fimmu.2018.01900","volume":"9","author":"P Bortolotti","year":"2018","unstructured":"Bortolotti P, Faure E, Kipnis E. Inflammasomes in tissue damages and immune disorders after trauma. Front Immunol. 2018;9:1900. https:\/\/doi.org\/10.3389\/fimmu.2018.01900.","journal-title":"Front Immunol"},{"issue":"11","key":"2508_CR13","doi-asserted-by":"publisher","first-page":"2164","DOI":"10.1002\/ijc.30833","volume":"141","author":"Y Liao","year":"2017","unstructured":"Liao Y, Tong L, Tang L, Wu S. The role of cold-inducible RNA binding protein in cell stress response. Int J Cancer. 2017;141(11):2164\u201373. https:\/\/doi.org\/10.1002\/ijc.30833.","journal-title":"Int J Cancer"},{"issue":"11","key":"2508_CR14","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1038\/nm.3368","volume":"19","author":"X Qiang","year":"2013","unstructured":"Qiang X, Yang WL, Wu R, Zhou M, Jacob A, Dong W, et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med. 2013;19(11):1489\u201395. https:\/\/doi.org\/10.1038\/nm.3368.","journal-title":"Nat Med"},{"issue":"2","key":"2508_CR15","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1189\/jlb.1205738","volume":"80","author":"B Gao","year":"2006","unstructured":"Gao B, Wang Y, Tsan MF. The heat sensitivity of cytokine-inducing effect of lipopolysaccharide. J Leukoc Biol. 2006;80(2):359\u201366. https:\/\/doi.org\/10.1189\/jlb.1205738.","journal-title":"J Leukoc Biol"},{"issue":"11","key":"2508_CR16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142203","volume":"10","author":"OR Shamaa","year":"2015","unstructured":"Shamaa OR, Mitra S, Gavrilin MA, Wewers MD. Monocyte caspase-1 is released in a stable, active high molecular weight complex distinct from the unstable cell lysate-activated caspase-1. PLoS One. 2015;10(11):e0142203. https:\/\/doi.org\/10.1371\/journal.pone.0142203.","journal-title":"PLoS One"},{"issue":"6","key":"2508_CR17","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1038\/s41589-019-0277-7","volume":"15","author":"RC Coll","year":"2019","unstructured":"Coll RC, Hill JR, Day CJ, Zamoshnikova A, Boucher D, Massey NL, et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat Chem Biol. 2019;15(6):556\u20139. https:\/\/doi.org\/10.1038\/s41589-019-0277-7.","journal-title":"Nat Chem Biol"},{"issue":"1","key":"2508_CR18","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/imr.12286","volume":"265","author":"EI Elliott","year":"2015","unstructured":"Elliott EI, Sutterwala FS. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol Rev. 2015;265(1):35\u201352. https:\/\/doi.org\/10.1111\/imr.12286.","journal-title":"Immunol Rev"},{"issue":"4","key":"2508_CR19","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1007\/s00281-013-0361-0","volume":"35","author":"I Mitroulis","year":"2013","unstructured":"Mitroulis I, Kambas K, Ritis K. Neutrophils, IL-1beta, and gout: is there a link? Semin Immunopathol. 2013;35(4):501\u201312. https:\/\/doi.org\/10.1007\/s00281-013-0361-0.","journal-title":"Semin Immunopathol"},{"issue":"1","key":"2508_CR20","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1111\/imr.12289","volume":"265","author":"KM Storek","year":"2015","unstructured":"Storek KM, Monack DM. Bacterial recognition pathways that lead to inflammasome activation. Immunol Rev. 2015;265(1):112\u201329. https:\/\/doi.org\/10.1111\/imr.12289.","journal-title":"Immunol Rev"},{"key":"2508_CR21","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.cca.2016.11.016","volume":"464","author":"L Yu","year":"2017","unstructured":"Yu L, Li QH, Deng F, Yu ZW, Luo XZ, Sun JL. Synovial fluid concentrations of cold-inducible RNA-binding protein are associated with severity in knee osteoarthritis. Clin Chim Acta. 2017;464:44\u20139. https:\/\/doi.org\/10.1016\/j.cca.2016.11.016.","journal-title":"Clin Chim Acta"},{"issue":"1","key":"2508_CR22","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1111\/1756-185X.12892","volume":"21","author":"IS Yoo","year":"2018","unstructured":"Yoo IS, Lee SY, Park CK, Lee JC, Kim Y, Yoo SJ, et al. Serum and synovial fluid concentrations of cold-inducible RNA-binding protein in patients with rheumatoid arthritis. Int J Rheum Dis. 2018;21(1):148\u201354. https:\/\/doi.org\/10.1111\/1756-185X.12892.","journal-title":"Int J Rheum Dis"},{"issue":"9","key":"2508_CR23","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.3899\/jrheum.180855","volume":"46","author":"BM Alberts","year":"2019","unstructured":"Alberts BM, Barber JS, Sacre SM, Davies KA, Ghezzi P, Mullen LM. Precipitation of soluble uric acid is necessary for in vitro activation of the NLRP3 inflammasome in primary human monocytes. J Rheumatol. 2019;46(9):1141\u201350. https:\/\/doi.org\/10.3899\/jrheum.180855.","journal-title":"J Rheumatol"},{"issue":"1","key":"2508_CR24","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1002\/JLB.3MIR1118-443R","volume":"106","author":"M Aziz","year":"2019","unstructured":"Aziz M, Brenner M, Wang P. Extracellular CIRP (eCIRP) and inflammation. J Leukoc Biol. 2019;106(1):133\u201346. https:\/\/doi.org\/10.1002\/JLB.3MIR1118-443R.","journal-title":"J Leukoc Biol"},{"issue":"1","key":"2508_CR25","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1111\/imr.12833","volume":"294","author":"G Cabau","year":"2020","unstructured":"Cabau G, Crisan TO, Kluck V, Popp RA, Joosten LAB. Urate-induced immune programming: consequences for gouty arthritis and hyperuricemia. Immunol Rev. 2020;294(1):92\u2013105. https:\/\/doi.org\/10.1111\/imr.12833.","journal-title":"Immunol Rev"},{"issue":"7","key":"2508_CR26","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1038\/ncprheum0531","volume":"3","author":"D Foell","year":"2007","unstructured":"Foell D, Wittkowski H, Roth J. Mechanisms of disease: a 'DAMP' view of inflammatory arthritis. Nat Clin Pract Rheumatol. 2007;3(7):382\u201390. https:\/\/doi.org\/10.1038\/ncprheum0531.","journal-title":"Nat Clin Pract Rheumatol"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02508-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13075-021-02508-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02508-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:03:35Z","timestamp":1619395415000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-021-02508-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,26]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2508"],"URL":"https:\/\/doi.org\/10.1186\/s13075-021-02508-9","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-203514\/v1","asserted-by":"object"}]},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,26]]},"assertion":[{"value":"3 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval for this study (No. 29281) was provided by the Ethics Committee of Fukushima Medical University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"KM has received research grants from Chugai, Pfizer, and AbbVie. The rest of the authors declares that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"128"}}