{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:22:29Z","timestamp":1791566549072,"version":"4.3.4"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":1486,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["108045\/Z\/15\/Z"],"award-info":[{"award-number":["108045\/Z\/15\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Infection of human macrophages with Salmonella enterica serovar Typhimurium (S. Typhimurium) leads to inflammasome activation. Inflammasomes are multiprotein complexes facilitating caspase-1 activation and subsequent gasdermin D\u2013mediated cell death and IL-1\u03b2 and IL-18 cytokine release. The NAIP\/NLRC4 inflammasome is activated by multiple bacterial protein ligands, including flagellin from the flagellum and the needle protein PrgI from the S. Typhimurium type III secretion system. In this study, we show that transfected ultrapure flagellin from S. Typhimurium induced cell death and cytokine secretion in THP-1 cells and primary human monocyte-derived macrophages. In THP-1 cells, NAIP\/NLRC4 and NLRP3 played redundant roles in inflammasome activation during infection with S. Typhimurium. Knockout of NAIP or NLRC4 in THP-1 cells revealed that flagellin, but not PrgI, now activated the NLRP3 inflammasome through a reactive oxygen species\u2013 and\/or cathepsin-dependent mechanism that was independent of caspase-4\/5 activity. In conclusion, our data suggest that NLRP3 can be activated by flagellin to act as a \u201csafety net\u201d to maintain inflammasome activation under conditions of suboptimal NAIP\/NLRC4 activation, as observed in THP-1 cells, possibly explaining the redundant role of NLRP3 and NAIP\/NLRC4 during S. Typhimurium infection.<\/jats:p>","DOI":"10.4049\/jimmunol.2000382","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T16:41:16Z","timestamp":1609346476000},"page":"631-640","source":"Crossref","is-referenced-by-count":112,"title":["<i>Salmonella<\/i> Flagellin Activates NAIP\/NLRC4 and Canonical NLRP3 Inflammasomes in Human Macrophages"],"prefix":"10.1093","volume":"206","author":[{"given":"Anna M","family":"Gram","sequence":"first","affiliation":[{"name":"Immunology Catalyst Programme, GlaxoSmithKline , Stevenage SG1 2NY ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9758-9944","authenticated-orcid":false,"given":"John A","family":"Wright","sequence":"additional","affiliation":[{"name":"Immunology Catalyst Programme, GlaxoSmithKline , Stevenage SG1 2NY ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-9868","authenticated-orcid":false,"given":"Robert J","family":"Pickering","sequence":"additional","affiliation":[{"name":"Immunology Catalyst Programme, GlaxoSmithKline , Stevenage SG1 2NY ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3255-8642","authenticated-orcid":false,"given":"Nathaniel L","family":"Lam","sequence":"additional","affiliation":[{"name":"Immunology Catalyst Programme, GlaxoSmithKline , Stevenage SG1 2NY ,","place":["United Kingdom"]},{"name":"School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College , Dublin 2 ,","place":["Ireland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3003-5872","authenticated-orcid":false,"given":"Lee M","family":"Booty","sequence":"additional","affiliation":[{"name":"Immunology Catalyst Programme, GlaxoSmithKline , Stevenage SG1 2NY ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0864-1182","authenticated-orcid":false,"given":"Steve J","family":"Webster","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, The University of Cambridge , Cambridge CB3 OES ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare E","family":"Bryant","sequence":"additional","affiliation":[{"name":"Immunology Catalyst Programme, GlaxoSmithKline , Stevenage SG1 2NY ,","place":["United Kingdom"]},{"name":"Department of Veterinary Medicine, The University of Cambridge , Cambridge CB3 OES ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,1]]},"reference":[{"key":"2025022610331324600_r1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/imr.12607","article-title":"The NLRC4 inflammasome","volume":"281","author":"Duncan","year":"2018","journal-title":"Immunol. 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