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

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

Author(s): 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;
Details: Publication Year 2022-02-01,Volume 55,Issue #3,Page 423-441.e9.
Journal Title: Immunity
Abstract: 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.
Publisher: Cell Press
Keywords: BAX and BAK; Covid-19; SARS-CoV-2; Tnf; Toll-like receptor; apoptosis; caspase-8; hemophagocytic lymphohistiocytosis; iNOS; interferon
Research Division(s): Inflammation; Immunology; Blood Cells And Blood Cancer; Infectious Diseases And Immune Defence
PubMed ID: 35139355
Link To PubMed Central Version: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822620/
Publisher's Version: https://doi.org/10.1016/j.immuni.2022.01.003
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2022-02-18 03:36:01

Last Modified: 2022-07-27 11:02:41