Simpson, Daniel S., Pang, Jiyi, Weir, Ashley ORCID: 0000-0002-3072-2616, Kong, Isabella Y., Fritsch, Melanie, Rashidi, Maryam, Cooney, James P., Davidson, Kathryn C., Speir, Mary, Djajawi, Tirta M., Hughes, Sebastian ORCID: 0000-0003-0084-5014, Mackiewicz, Liana, Dayton, Merle, Anderton, Holly, Doerflinger, Marcel, Deng, Yexuan, Huang, Allan Shuai, Conos, Stephanie A., Tye, Hazel, Chow, Seong H., Rahman, Arfatur ORCID: 0000-0001-8749-0337, Norton, Raymond S., Naderer, Thomas, Nicholson, Sandra E., Burgio, Gaetan, Man, Si Ming ORCID: 0000-0002-5079-2857, Groom, Joanna R., Herold, Marco J., Hawkins, Edwin D., Lawlor, Kate E., Strasser, Andreas, Silke, John ORCID: 0000-0002-7611-5774, Pellegrini, Marc, Kashkar, Hamid, Feltham, Rebecca ORCID: 0000-0001-8376-6869 and Vince, James E. (2022). Interferon-g primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway. Immunity, 55 (3). S. 423 - 452. CAMBRIDGE: CELL PRESS. ISSN 1097-4180

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Abstract

Cell death plays an important role during pathogen infections. Here, we report that interferon-g (IFNg) 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. IFNg-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Simpson, Daniel S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pang, JiyiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weir, AshleyUNSPECIFIEDorcid.org/0000-0002-3072-2616UNSPECIFIED
Kong, Isabella Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fritsch, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rashidi, MaryamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cooney, James P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Davidson, Kathryn C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speir, MaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Djajawi, Tirta M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hughes, SebastianUNSPECIFIEDorcid.org/0000-0003-0084-5014UNSPECIFIED
Mackiewicz, LianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dayton, MerleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anderton, HollyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doerflinger, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deng, YexuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huang, Allan ShuaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conos, Stephanie A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tye, HazelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chow, Seong H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahman, ArfaturUNSPECIFIEDorcid.org/0000-0001-8749-0337UNSPECIFIED
Norton, Raymond S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naderer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nicholson, Sandra E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burgio, GaetanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Man, Si MingUNSPECIFIEDorcid.org/0000-0002-5079-2857UNSPECIFIED
Groom, Joanna R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herold, Marco J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hawkins, Edwin D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lawlor, Kate E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strasser, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silke, JohnUNSPECIFIEDorcid.org/0000-0002-7611-5774UNSPECIFIED
Pellegrini, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashkar, HamidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feltham, RebeccaUNSPECIFIEDorcid.org/0000-0001-8376-6869UNSPECIFIED
Vince, James E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-687996
DOI: 10.1016/j.immuni.2022.01.003
Journal or Publication Title: Immunity
Volume: 55
Number: 3
Page Range: S. 423 - 452
Date: 2022
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-4180
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NITRIC-OXIDE SYNTHASE; NLRP3 INFLAMMASOME ACTIVATION; TUMOR-NECROSIS-FACTOR; IFN-GAMMA; INDUCED APOPTOSIS; S-NITROSYLATION; SIGNALING PATHWAYS; TOXOPLASMA-GONDII; MOLECULAR SWITCH; MICE LACKINGMultiple languages
ImmunologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68799

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