| First Author | Simpson DS | Year | 2022 |
| Journal | Immunity | Volume | 55 |
| Issue | 3 | Pages | 423-441.e9 |
| PubMed ID | 35139355 | Mgi Jnum | J:324833 |
| Mgi Id | MGI:7281911 | Doi | 10.1016/j.immuni.2022.01.003 |
| Citation | Simpson DS, et al. (2022) Interferon-gamma primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway. Immunity 55(3):423-441.e9 |
| abstractText | Cell death plays an important role during pathogen infections. Here, we report that interferon-gamma (IFNgamma) 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. IFNgamma-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. |
