期刊
IMMUNITY
卷 55, 期 3, 页码 423-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2022.01.003
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资金
- National Health and Medical Research Council (NHMRC) of Australia [1145788, 1101405, 1162765, 1165591, 1143105, 1183848, 1137989, 1183070, 1181089, 1182649, 1194144, 1175011, 1107149, 1195038, 101671]
- German Research Foundation [SFB1403, 414786233, 1141466, 1020363, 1144014, 1159488]
- Leukemia and Lymphoma Society [LLS SCOR7015-18]
- Australian Research Council (ARC) [FT190100266, FT170100313]
- Monash Graduate Scholarship (CF-MGS) from Monash University
- NHMRC [1156095]
- National Collaborative Research Infrastructure Strategy (NCRIS) via Phenom-ics Australia
- Walter and Eliza Hall Institute of Medical Research
- Galbraith Family Charitable Trust
- Australian Government Independent Research Institute Infrastructure Support Scheme
- Victorian State Government Operational Infrastructure Support Scheme, Australia
- National Health and Medical Research Council of Australia [1182649, 1183070, 1183848, 1194144, 1195038, 1165591, 1162765, 1156095, 1137989, 1181089, 1175011] Funding Source: NHMRC
- Australian Research Council [FT190100266, FT170100313] Funding Source: Australian Research Council
Cell death is crucial in pathogen infections. IFNg sensitizes macrophages to TLR-induced death by triggering macrophage-intrinsic death ligands and caspase-8 enzymatic activity. This process requires BAX and BAK, the mitochondrial apoptotic effectors.
Cell death plays an important role during pathogen infections. Here, we report that interferon-g (IFNg) 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. IFNg-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.
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