@article{a84dcfdc33aa42dabfe423a5cd30473d,
title = "Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway",
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.",
keywords = "apoptosis, BAX and BAK, caspase-8, COVID-19, hemophagocytic lymphohistiocytosis, iNOS, interferon, SARS-CoV-2, TNF, Toll-like receptor",
author = "Simpson, {Daniel S.} and Jiyi Pang and Ashley Weir and Kong, {Isabella Y.} and Melanie Fritsch and Maryam Rashidi and Cooney, {James P.} and Davidson, {Kathryn C.} and Mary Speir and Djajawi, {Tirta M.} and Sebastian Hughes and Liana Mackiewicz and Merle Dayton and Holly Anderton and Marcel Doerflinger and Yexuan Deng and Huang, {Allan Shuai} and Conos, {Stephanie A.} and Hazel Tye and Chow, {Seong H.} and Arfatur Rahman and Norton, {Raymond S.} and Thomas Naderer and Nicholson, {Sandra E.} and Gaetan Burgio and Man, {Si Ming} and Groom, {Joanna R.} and Herold, {Marco J.} and Hawkins, {Edwin D.} and Lawlor, {Kate E.} and Andreas Strasser and John Silke and Marc Pellegrini and Hamid Kashkar and Rebecca Feltham and Vince, {James E.}",
note = "Funding Information: We thank Associate Professor G. Dewson for valuable experimental advice and critical reading of the manuscript and Dr. P. Bouillet for kind donation of Pmaip1 −/− and Bid −/− mice. We gratefully acknowledge grant support from the National Health and Medical Research Council (NHMRC) of Australia (project grants: 1145788 to J.E.V., K.E.L.; 1101405 to J.E.V.; 1162765 to K.E.L.; 1165591 to E.D.H.; 1143105 to M.J.H. and A.S.; 1183848 to T.N; 1137989 to J.R.G; ideas grants: 1183070 to J.E.V.; 1181089 to K.E.L.; 1182649 to J.R.G; investigator grants: 1194144 to H.A.; 1175011 to M.P.; 1107149 & 1195038 to J.S.; program grant 101671 to A.S.), the German Research Foundation ( SFB1403 , project no. 414786233 to H.K.), fellowships ( 1141466 to J.E.V.; 1020363 to A.S.; 1144014 to S.A.C.; 1159488 to E.D.H.), and the Leukemia and Lymphoma Society ( LLS SCOR 7015-18 to A.S., M.J.H., and J.S.). K.E.L. and T.F are Australian Research Council (ARC) Future Fellows ( FT190100266 to K.E.L and FT170100313 to T.N.). A.R. is supported by the Co-Funded Monash Graduate Scholarship (CF-MGS) from Monash University. M.J.H. is an NHMRC Senior Research Fellow ( 1156095 ). G.B. is funded by the National Collaborative Research Infrastructure Strategy (NCRIS) via Phenomics Australia . D.S.S. is supported by a philanthropic PhD scholarship from the Walter and Eliza Hall Institute of Medical Research . R.F. is supported by the Galbraith Family Charitable Trust . This work was also supported by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support Scheme , Australia. Funding Information: We thank Associate Professor G. Dewson for valuable experimental advice and critical reading of the manuscript and Dr. P. Bouillet for kind donation of Pmaip1?/? and Bid?/? mice. We gratefully acknowledge grant support from the National Health and Medical Research Council (NHMRC) of Australia (project grants: 1145788 to J.E.V. K.E.L.; 1101405 to J.E.V.; 1162765 to K.E.L.; 1165591 to E.D.H.; 1143105 to M.J.H. and A.S.; 1183848 to T.N; 1137989 to J.R.G; ideas grants: 1183070 to J.E.V.; 1181089 to K.E.L.; 1182649 to J.R.G; investigator grants: 1194144 to H.A.; 1175011 to M.P.; 1107149 & 1195038 to J.S.; program grant 101671 to A.S.), the German Research Foundation (SFB1403, project no. 414786233 to H.K.), fellowships (1141466 to J.E.V.; 1020363 to A.S.; 1144014 to S.A.C.; 1159488 to E.D.H.), and the Leukemia and Lymphoma Society (LLS SCOR 7015-18 to A.S. M.J.H. and J.S.). K.E.L. and T.F are Australian Research Council (ARC) Future Fellows (FT190100266 to K.E.L and FT170100313 to T.N.). A.R. is supported by the Co-Funded Monash Graduate Scholarship (CF-MGS) from Monash University. M.J.H. is an NHMRC Senior Research Fellow (1156095). G.B. is funded by the National Collaborative Research Infrastructure Strategy (NCRIS) via Phenomics Australia. D.S.S. is supported by a philanthropic PhD scholarship from the Walter and Eliza Hall Institute of Medical Research. R.F. is supported by the Galbraith Family Charitable Trust. This work was also supported by operational infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support Scheme, Australia. The project was conceived by D.S.S. J.E.V. and R.F.; the experiments were designed by D.S.S. J.E.V. and R.F.; and the manuscript was written by D.S.S. J.E.V. and R.F. Experiments were performed by D.S.S. J.P. A.W. I.Y.K. M.F. M.R. J.P.C. K.C.D. M.S. T.M.D. S.H. L.M. M.D. H.A. M.D. Y.D. S.A.C. H.T. A.R. S.H.C. K.E.L. R.F. and J.E.V. Expert advice, essential mice, and reagents were provided by A.S.H. R.S.N. T.N. S.E.N. G.B. S.M.M. J.R.G. M.J.H. E.D.H. A.S. J.S. M.P. and H.K. All authors assisted with data interpretation and manuscript editing. The authors declare that D.S.S. J.P. A.W. I.Y.K. M.R. J.P.C. K.C.D. S.H. H.A. M.D. Y.D. L.M. M.D. A.S.H. S.E.N. J.R.G. M.J.H. E.D.H. A.S. J.S. M.P. R.F. and J.E.V. are employees or former employees of the Walter and Eliza Hall Medical Institute, which receives milestone payments from Genentech and AbbVie for the development of ABT-199 for cancer therapy. J.E.V. sits on the advisory board of Avammune Therapeutics. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = mar,
day = "8",
doi = "10.1016/j.immuni.2022.01.003",
language = "English",
volume = "55",
pages = "423--441.e9",
journal = "Immunity",
issn = "1074-7613",
publisher = "Elsevier",
number = "3",
}
