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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Immunity 2022 ; 55 (3): 423-441.e9 Nephropedia Template TP
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Interferon-gamma primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway #MMPMID35139355
Simpson DS; Pang J; Weir A; Kong IY; Fritsch M; Rashidi M; Cooney JP; Davidson KC; Speir M; Djajawi TM; Hughes S; Mackiewicz L; Dayton M; Anderton H; Doerflinger M; Deng Y; Huang AS; Conos SA; Tye H; Chow SH; Rahman A; Norton RS; Naderer T; Nicholson SE; Burgio G; Man SM; Groom JR; Herold MJ; Hawkins ED; Lawlor KE; Strasser A; Silke J; Pellegrini M; Kashkar H; Feltham R; Vince JE
Immunity 2022[Mar]; 55 (3): 423-441.e9 PMID35139355show ga
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.