Journal article
Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway
DS Simpson, J Pang, A Weir, IY Kong, M Fritsch, M Rashidi, JP Cooney, KC Davidson, M Speir, TM Djajawi, S Hughes, L Mackiewicz, M Dayton, H Anderton, M Doerflinger, Y Deng, AS Huang, SA Conos, H Tye, SH Chow Show all
Immunity | Published : 2022
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..
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Awarded by Genentech
Funding Acknowledgements
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<SUP>-/-</SUP> and Bid<SUP>-/-</SUP>mice. We gratefully acknowledge grant support from the National Health and Medical Research Council (NHMRC) of Australia (proj-ect 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 Foun-dation (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 Leu-kemia 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 Phenom-ics 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 opera-tional infrastructure grants through the Australian Government Independent Research Institute Infrastructure Support Scheme and the Victorian State Gov-ernment Operational Infrastructure Support Scheme, Australia.