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• W4288702331 abstract "Abstract The inflammatory cytokine tumor necrosis factor (TNF) is associated with host defense against many intracellular pathogens, including Legionella pneumophila. Legionella causes the severe pneumonia Legionnaires’ Disease and predominantly affects individuals with a suppressed immune system, such as those receiving therapeutic TNF blockade to treat autoinflammatory disorders. 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 many downstream activities of TNF contribute to control of intracellular bacterial pathogens like Legionella . In this study, we demonstrate that TNF signaling licenses macrophages to die rapidly in response to Legionella 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 Legionella infection. These findings reveal a TNF-dependent mechanism in macrophages for the activation of rapid cell death that is collectively mediated by caspases-1, -8, and -11 and subsequent restriction of Legionella infection." @default.
• W4288702331 created "2022-07-30" @default.
• W4288702331 creator A5028965776 @default.
• W4288702331 creator A5059475430 @default.
• W4288702331 creator A5070897701 @default.
• W4288702331 creator A5071496324 @default.
• W4288702331 date "2022-07-29" @default.
• W4288702331 modified "2023-10-14" @default.
• W4288702331 title "TNF licenses macrophages to undergo rapid caspase-1, -11, and -8-mediated cell death that restricts <i>Legionella pneumophila</i> infection" @default.
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• W4288702331 doi "https://doi.org/10.1101/2022.07.29.501970" @default.
• W4288702331 hasPublicationYear "2022" @default.
• W4288702331 type Work @default.
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• W4288702331 hasAuthorship W4288702331A5028965776 @default.
• W4288702331 hasAuthorship W4288702331A5059475430 @default.

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