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TNF induces pro-inflammatory gene expression, cellular proliferation, and survival signals in certain contexts, but can also trigger programmed cell death in others. It remains unclear, however, which of the pleiotropic functions of TNF mediate control of intracellular bacterial pathogens like <jats:italic>Legionella<\/jats:italic>. In this study, we demonstrate that TNF signaling licenses macrophages to die rapidly in response to <jats:italic>Legionella<\/jats:italic> infection. We find that TNF-licensed cells undergo rapid gasdermin-dependent, pyroptotic death downstream of inflammasome activation. We also find that TNF signaling upregulates components of the inflammasome response, and that the caspase-11-mediated non-canonical inflammasome is the first inflammasome to be activated, with caspase-1 and caspase-8 mediating delayed pyroptotic death. We find that all three caspases are collectively required for optimal TNF-mediated restriction of bacterial replication in macrophages. Furthermore, caspase-8 is required for control of pulmonary <jats:italic>Legionella<\/jats:italic> infection. These findings reveal a TNF-dependent mechanism in macrophages for activating rapid cell death that is collectively mediated by caspases-1, -8, and -11 and subsequent restriction of <jats:italic>Legionella<\/jats:italic> infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010767","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T20:23:03Z","timestamp":1686082983000},"page":"e1010767","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["TNF licenses macrophages to undergo rapid caspase-1, -11, and -8-mediated cell death that restricts Legionella pneumophila infection"],"prefix":"10.1371","volume":"19","author":[{"given":"Tzvi Y.","family":"Pollock","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor R.","family":"V\u00e1zquez Marrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor E.","family":"Brodsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5214-9577","authenticated-orcid":true,"given":"Sunny","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"issue":"11","key":"ppat.1010767.ref001","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1038\/ni1528","article-title":"Pathogen subversion of cell-intrinsic innate immunity","volume":"8","author":"CR Roy","year":"2007","journal-title":"Nat Immunol"},{"issue":"6","key":"ppat.1010767.ref002","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/1074-7613(95)90001-2","article-title":"Tumor necrosis factor-alpha is required in the protective immune response 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