{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:45:53Z","timestamp":1791917153016,"version":"4.3.4"},"reference-count":52,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"959","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NINDS P30NS047101"],"award-info":[{"award-number":["NINDS P30NS047101"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD030505 & S10OD036455"],"award-info":[{"award-number":["S10OD030505 & S10OD036455"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI155869"],"award-info":[{"award-number":["R01AI155869"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01HL152958"],"award-info":[{"award-number":["P01HL152958"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["Career Development Award"],"award-info":[{"award-number":["Career Development Award"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2026,10,13]]},"abstract":"<jats:p>\n                    The Nod-like receptor family pyrin domain\u2013containing 3 (NLRP3) inflammasome is a cytosolic multiprotein immune sensor that is restrained from assembling at steady state. Mutations in\n                    <jats:italic toggle=\"yes\">NLRP3<\/jats:italic>\n                    associated with cryopyrin-associated periodic syndrome (CAPS) enhance inflammasome formation and activation, resulting in neutrophil-predominant systemic and tissue inflammation. Here, we investigated how gasdermin D (GSDMD) and GSDME drive interleukin-1\u03b2 (IL-1\u03b2) release, pyroptosis, and autoinflammation during constitutive and canonical NLRP3 activation in neutrophils. Mass cytometry analysis of neutrophils from patients with CAPS revealed heterogeneous subtypes with differing amounts of intracellular IL-1\u03b2. In mice, neutrophil-specific expression of activating\n                    <jats:italic toggle=\"yes\">Nlrp3<\/jats:italic>\n                    mutations orthologous to those in patients with CAPS uncovered nonredundant roles for GSDMD and GSDME downstream of inflammasome activation. Combined deletion of\n                    <jats:italic toggle=\"yes\">Gsdmd<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Gsdme<\/jats:italic>\n                    in these CAPS models reduced IL-1\u03b2 secretion, prevented pyroptosis, and mitigated autoinflammation. Loss of both GSDMD and GSDME reduced caspase-1 cleavage and pro\u2013IL-1\u03b2 processing downstream of NLRP3 activation, whereas GSDMD deficiency alone increased cleavage of GSDME and caspase-8. Clusters of GSDMD and GSDME were closely associated with one another at the plasma membrane of activated neutrophils from CAPS mice. These findings indicate that the coordinated actions of membrane-associated GSDMD and GSDME reinforce cytosolic NLRP3 inflammasome activation to promote IL-1\u03b2 secretion, lytic cell death, and autoinflammation.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.aec1743","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:58:13Z","timestamp":1791914293000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Clusters of GSDMD and GSDME mediate neutrophil pyroptosis in cryopyrin-associated periodic syndrome"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3116-0203","authenticated-orcid":true,"given":"ZheHao","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahand","family":"Salari Namin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."},{"name":"Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-8487","authenticated-orcid":true,"given":"Janset","family":"Onyuru","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirav","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"name":"Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0343-3990","authenticated-orcid":true,"given":"Jonathan Rodrigo","family":"Erlich","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8662-9840","authenticated-orcid":true,"given":"Cameron J.","family":"Nowell","sequence":"additional","affiliation":[{"name":"Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5628-0243","authenticated-orcid":true,"given":"Jennifer","family":"Santini","sequence":"additional","affiliation":[{"name":"UCSD School of Medicine Microscopy Core, UC San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3089-5434","authenticated-orcid":true,"given":"Marisela","family":"Guaderrama","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2407-435X","authenticated-orcid":true,"given":"Maxine","family":"Nanthavongdouangsy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5465-3670","authenticated-orcid":true,"given":"Jamie Casey","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori","family":"Broderick","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2045-4117","authenticated-orcid":true,"given":"Catherine","family":"Hedrick","sequence":"additional","affiliation":[{"name":"Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA."},{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1832-9050","authenticated-orcid":true,"given":"William B.","family":"Kiosses","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1873-0277","authenticated-orcid":true,"given":"Sergio D.","family":"Catz","sequence":"additional","affiliation":[{"name":"Scripps Research Institute, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1109-1836","authenticated-orcid":true,"given":"Ratnesh","family":"Lal","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"name":"Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"name":"Materials Science and Engineering Program, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6908-0860","authenticated-orcid":true,"given":"Yanfang Peipei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."},{"name":"Immunology Center of Georgia, Augusta University, Augusta, GA 30912, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0885-3599","authenticated-orcid":true,"given":"Ben A.","family":"Croker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8609-2548","authenticated-orcid":true,"given":"Hal M.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.22491"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13292"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202154277"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03478-3"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng756"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20231200"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202154339"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202154446"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abj3859"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI147076"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.05.005"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI71543"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.06.028"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2101189118"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44669-y"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj1397"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevE.72.021914"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545655"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature16959"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11588"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01656-1"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545772"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13683"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27692-9"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36626-6"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800788"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.42139"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108998"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000735"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09753-2"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.03.008"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05991-z"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09222-5"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-02024-3"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aee4587"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.07.027"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002702"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0550-7"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_2_41_2","doi-asserted-by":"crossref","unstructured":"U. Schmidt M. Weigert C. Broaddus G. Myers \u201cCell detection with star-convex polygons\u201d in Medical Image Computing and Computer Assisted Intervention\u2013MICCAI 2018 vol. 11071 of Lecture Notes in Computer Science (Springer 2018) pp. 265\u2013273.","DOI":"10.1007\/978-3-030-00934-2_30"},{"key":"e_1_3_2_42_2","unstructured":"W. Chang J. Cheng J. Allaire Y. Xie J. McPherson shiny: Web Application Framework for R. R package version 0.14.2 (2016)."},{"key":"e_1_3_2_43_2","first-page":"8","article-title":"Plotrix: A package in the red light district of R","volume":"6","author":"Lemon J.","year":"2006","unstructured":"J. Lemon, Plotrix: A package in the red light district of R. R News 6, 8\u201312 (2006).","journal-title":"R News"},{"key":"e_1_3_2_44_2","unstructured":"R Core Team R: A language and environment for statistical computing (R Foundation for Statistical Computing 2020)."},{"key":"e_1_3_2_45_2","unstructured":"H. Wickham R. Fran\u00e7ois L. Henry K. M\u00fcller dplyr: A Grammar of Data Manipulation. R package version 1.0.6 (2021); https:\/\/CRAN.R-project.org\/package=dplyr."},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2015.1081323"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-017-4102-2"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nano.2008.07.002"},{"key":"e_1_3_2_49_2","first-page":"181","article-title":"Gwyddion: An open-source software for SPM data analysis","volume":"10","author":"Ne\u010das D.","year":"2012","unstructured":"D. Ne\u010das, P. Klapetek, Gwyddion: An open-source software for SPM data analysis. Cent. Eur. J. Phys. 10, 181\u2013188 (2012).","journal-title":"Cent. Eur. J. Phys."},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2015.1084453"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.4881683"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2449-4_16"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aao1716"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.aec1743","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:58:20Z","timestamp":1791914300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.aec1743"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,13]]},"references-count":52,"journal-issue":{"issue":"959","published-print":{"date-parts":[[2026,10,13]]}},"alternative-id":["10.1126\/scisignal.aec1743"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.aec1743","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,13]]},"assertion":[{"value":"2025-09-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-16","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaec1743"}}