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Using a murine model of CpG-DNA induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome, or downstream caspase-1, prevented MAS-mediated upregulation of plasma IL-18 but interestingly did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore IL-1 receptor blockade with IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that in the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18, a key cytokine in clinical cases of MAS, but was not a driving factor in the pathogenesis of CpG-induced MAS.<\/jats:p>","DOI":"10.1101\/2024.02.27.582284","type":"posted-content","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T16:10:14Z","timestamp":1709309414000},"source":"Crossref","is-referenced-by-count":4,"title":["The NLRP3 inflammasome is essential for IL-18 production in a murine model of macrophage activation syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9850-1134","authenticated-orcid":false,"given":"Tara A.","family":"Gleeson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7499-6769","authenticated-orcid":false,"given":"Christina","family":"Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2372-2968","authenticated-orcid":false,"given":"Catherine B.","family":"Lawrence","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2250-2381","authenticated-orcid":false,"given":"David","family":"Brough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9646-4456","authenticated-orcid":false,"given":"Stuart M.","family":"Allan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1108-3422","authenticated-orcid":false,"given":"Jack P.","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024030408400472000_2024.02.27.582284v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2026131"},{"key":"2024030408400472000_2024.02.27.582284v1.2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01446"},{"key":"2024030408400472000_2024.02.27.582284v1.3","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/art.39332","article-title":"2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism\/American College of Rheumatology\/Paediatric Rheumatology International Trials Organisation Collaborative Initiative","volume":"68","year":"2016","journal-title":"Arthritis Rheumatol"},{"key":"2024030408400472000_2024.02.27.582284v1.4","doi-asserted-by":"crossref","first-page":"428","DOI":"10.2177\/jsci.30.428","article-title":"Macrophage activation syndrome associated with adult-onset Still\u2019s disease","volume":"30","year":"2007","journal-title":"Nihon Rinsho Meneki Gakkai Kaishi"},{"key":"2024030408400472000_2024.02.27.582284v1.5","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s10067-017-3625-6","article-title":"Macrophage activation syndrome in systemic lupus erythematosus: a multicenter, case-control study in China","volume":"37","year":"2018","journal-title":"Clin Rheumatol"},{"key":"2024030408400472000_2024.02.27.582284v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.09.019"},{"key":"2024030408400472000_2024.02.27.582284v1.7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00524"},{"key":"2024030408400472000_2024.02.27.582284v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-009-0261-1"},{"key":"2024030408400472000_2024.02.27.582284v1.9","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.hoc.2015.06.007","article-title":"Pathogenesis of Hemophagocytic Lymphohistiocytosis","volume":"29","year":"2015","journal-title":"Hematol Oncol Clin North Am"},{"key":"2024030408400472000_2024.02.27.582284v1.10","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41435-020-0098-4","article-title":"The genetics of macrophage activation syndrome","volume":"21","year":"2020","journal-title":"Genes Immun"},{"key":"2024030408400472000_2024.02.27.582284v1.11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00119"},{"key":"2024030408400472000_2024.02.27.582284v1.12","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1999.01504.x"},{"key":"2024030408400472000_2024.02.27.582284v1.13","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/cei.13543","article-title":"The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis\/macrophage activation syndrome - 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