Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway

Daniel S. Simpson, Jiyi Pang, Ashley Weir, Isabella Y. Kong, Melanie Fritsch, Maryam Rashidi, James P. Cooney, Kathryn C. Davidson, Mary Speir, Tirta M. Djajawi, Sebastian Hughes, Liana Mackiewicz, Merle Dayton, Holly Anderton, Marcel Doerflinger, Yexuan Deng, Allan Shuai Huang, Stephanie A. Conos, Hazel Tye, Seong H. ChowArfatur Rahman, Raymond S. Norton, Thomas Naderer, Sandra E. Nicholson, Gaetan Burgio, Si Ming Man, Joanna R. Groom, Marco J. Herold, Edwin D. Hawkins, Kate E. Lawlor, Andreas Strasser, John Silke, Marc Pellegrini, Hamid Kashkar, Rebecca Feltham*, James E. Vince*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    61 Citations (Scopus)


    Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8 reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase (iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophage killing required iNOS, which licensed apoptotic caspase-8 activity and reduced the BAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induced disease in mice, while caspase-8 caused lethality independent of iNOS in a model of hemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licenses programmed cell death, which may explain how nitric oxide impacts disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.

    Original languageEnglish
    Pages (from-to)423-441.e9
    Issue number3
    Publication statusPublished - 8 Mar 2022


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