ArticleImmunity2022
Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway.
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Article in Immunity, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86citing papers in PubMed
19.7field-weighted citation impact, top 1% of its field
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Who cites it
86 citing papers in PubMed, 132 citations in OpenAlex.
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- Proteolytic activation of executioner caspase-3 and -7 regulates different physiological processes in mice.The EMBO journal · 2026Article
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- Asiatic Acid AttenuatesInternational journal of molecular sciences · 2026Article
- Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights.Immunity & inflammation · 2026Review
- The role of PANoptosis in diabetes and its complications: mechanisms and therapeutic prospects.Frontiers in immunology · 2026Review
- Prior Exposure of Airway Epithelial Cells to Mycobacteria Reduces Subsequent <italic>Mycobacterium tuberculosis</italic> Infection and Resulting Inflammation.Journal of innate immunity · 2026Article
- NIR-controlled photothermal intelligent nanozyme synergizes catalysis and gas therapy for multidimensional treatment of inflammatory bowel disease.Journal of nanobiotechnology · 2025Article
- Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection.Nature communications · 2025Article
- Regulation of inflammatory processes by caspases.Nature reviews. Molecular cell biology · 2025Review
- The causal relationship between 91 inflammatory cytokines and chronic pancreatitis, and the mediating role of 1400 metabolites.Medicine · 2025Article
- Cannabinoid Receptor 2 (CB2) in Macrophages: A Promising Clinical Target for Immune Disorders.International journal of molecular sciences · 2025Review
- Increased Dipeptidyl Peptidase-4 Promotes Adipose Inflammation and Dysfunction in Mice Under Chronic Stress.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
36 authors at 7 institutions in 3 countries.
Daniel S SimpsonThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Jiyi PangThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia; College of Life Sciences, Nankai University, Tianjin, 300071, China.
Ashley WeirThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Isabella Y KongThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Melanie FritschInstitute for Molecular Immunology, Centre for Molecular Medicine Cologne and Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, 50931, Germany.
Maryam RashidiThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
James P CooneyThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Kathryn C DavidsonThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Mary SpeirCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia.
Tirta M DjajawiCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia.
Sebastian HughesThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Liana MackiewiczThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
Merle DaytonThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
Holly AndertonThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Marcel DoerflingerThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Yexuan DengThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Allan Shuai HuangThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Stephanie A ConosCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia.
Hazel TyeCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia.
Seong H ChowThe Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Arfatur RahmanMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
Raymond S NortonMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia; ARC Centre for Fragment-Based Design, Monash University, Parkville, VIC, 3052, Australia.
Thomas NadererThe Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
Sandra E NicholsonThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Gaetan BurgioDepartment of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia.
Si Ming ManDepartment of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 2601, Australia.
Joanna R GroomThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Marco J HeroldThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Edwin D HawkinsThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Kate E LawlorCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia.
Andreas StrasserThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
John SilkeThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Marc PellegriniThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Hamid KashkarInstitute for Molecular Immunology, Centre for Molecular Medicine Cologne and Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases, University of Cologne, Cologne, 50931, Germany.
Rebecca FelthamThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia. Electronic address: feltham.r@wehi.edu.au.
James E VinceThe Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia. Electronic address: vince@wehi.edu.au.
The University of Melbourne · AUHudson Institute of Medical Research · AUAustralian National University · AUAustralian Regenerative Medicine Institute · AUMonash University · AUUniversity of Cologne · DEWalter and Eliza Hall Institute of Medical Research · AU
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
Animalsbcl-2-Associated X Proteinbcl-2 Homologous Antagonist-Killer ProteinCaspase 8Cells, CulturedCOVID-19Cytotoxicity, ImmunologicHumansInterferon-gammaLymphohistiocytosis, HemophagocyticMacrophage ActivationMacrophagesMiceMice, Inbred C57BLMice, KnockoutMitochondriabcl-2-Associated X Proteinbcl-2 Homologous Antagonist-Killer ProteinCaspase 8Interferon-gammaNitric Oxide Synthase Type IIPathogen-Associated Molecular Pattern MoleculesapoptosisBAX and BAKcaspase-8COVID-19hemophagocytic lymphohistiocytosisiNOSinterferonSARS-CoV-2TNFToll-like receptor
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