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

Daniel S. Simpson; Jiyi Pang; Ashley Weir; Isabella Y. Kong; Melanie Fritsch; Maryam Rashidi; James P. Cooney; Kathryn C. Davidson; Mary Speir; Tirta M. Djajawi; Sebastian Hughes; Liana Mackiewicz; Merle Dayton; Holly Anderton; Marcel Doerflinger; Yexuan Deng; Allan Shuai Huang; Stephanie A. Conos; Hazel Tye; Seong H. Chow; Arfatur Rahman; Raymond S. Norton; Thomas Naderer; Sandra E. Nicholson; Gaetan Burgio; Si Ming Man; Joanna R. Groom; Marco J. Herold; Edwin D. Hawkins; Kate E. Lawlor; Andreas Strasser; John Silke; Marc Pellegrini; Hamid Kashkar; Rebecca Feltham; James E. Vince

doi:10.1016/j.immuni.2022.01.003

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

Daniel S. Simpson, Jiyi Pang, Ashley Weir, Isabella Y. Kong, Melanie Fritsch, Maryam Rashidi, James P. Cooney, Kathryn C. Davidson, Mary Speir, Tirta M. Djajawi, Sebastian Hughes, Liana Mackiewicz, Merle Dayton, Holly Anderton, Marcel Doerflinger, Yexuan Deng, Allan Shuai Huang, Stephanie A. Conos, Hazel Tye, Seong H. ChowArfatur Rahman, Raymond S. Norton, Thomas Naderer, Sandra E. Nicholson, Gaetan Burgio, Si Ming Man, Joanna R. Groom, Marco J. Herold, Edwin D. Hawkins, Kate E. Lawlor, Andreas Strasser, John Silke, Marc Pellegrini, Hamid Kashkar, Rebecca Feltham^*, James E. Vince^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

87 Citations (Scopus)

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.

Original language	English
Pages (from-to)	423-441.e9
Journal	Immunity
Volume	55
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2022.01.003
Publication status	Published - 8 Mar 2022

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10.1016/j.immuni.2022.01.003

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Simpson, D. S., Pang, J., Weir, A., Kong, I. Y., Fritsch, M., Rashidi, M., Cooney, J. P., Davidson, K. C., Speir, M., Djajawi, T. M., Hughes, S., Mackiewicz, L., Dayton, M., Anderton, H., Doerflinger, M., Deng, Y., Huang, A. S., Conos, S. A., Tye, H., ... Vince, J. E. (2022). Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway. Immunity, 55(3), 423-441.e9. https://doi.org/10.1016/j.immuni.2022.01.003

@article{bd07afa86c44492e90e99bf4cfc7d2eb,

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 = "BAX and BAK, COVID-19, SARS-CoV-2, TNF, Toll-like receptor, apoptosis, caspase-8, hemophagocytic lymphohistiocytosis, iNOS, interferon",

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 = "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 = "Cell Press",

number = "3",

}

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 2022, 'Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway', Immunity, vol. 55, no. 3, pp. 423-441.e9. https://doi.org/10.1016/j.immuni.2022.01.003

TY - JOUR

T1 - Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway

AU - Simpson, Daniel S.

AU - Pang, Jiyi

AU - Weir, Ashley

AU - Kong, Isabella Y.

AU - Fritsch, Melanie

AU - Rashidi, Maryam

AU - Cooney, James P.

AU - Davidson, Kathryn C.

AU - Speir, Mary

AU - Djajawi, Tirta M.

AU - Hughes, Sebastian

AU - Mackiewicz, Liana

AU - Dayton, Merle

AU - Anderton, Holly

AU - Doerflinger, Marcel

AU - Deng, Yexuan

AU - Huang, Allan Shuai

AU - Conos, Stephanie A.

AU - Tye, Hazel

AU - Chow, Seong H.

AU - Rahman, Arfatur

AU - Norton, Raymond S.

AU - Naderer, Thomas

AU - Nicholson, Sandra E.

AU - Burgio, Gaetan

AU - Man, Si Ming

AU - Groom, Joanna R.

AU - Herold, Marco J.

AU - Hawkins, Edwin D.

AU - Lawlor, Kate E.

AU - Strasser, Andreas

AU - Silke, John

AU - Pellegrini, Marc

AU - Kashkar, Hamid

AU - Feltham, Rebecca

AU - Vince, James E.

PY - 2022/3/8

Y1 - 2022/3/8

N2 - 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.

AB - 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.

KW - BAX and BAK

KW - COVID-19

KW - SARS-CoV-2

KW - TNF

KW - Toll-like receptor

KW - apoptosis

KW - caspase-8

KW - hemophagocytic lymphohistiocytosis

KW - iNOS

KW - interferon

UR - http://www.scopus.com/inward/record.url?scp=85125622238&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2022.01.003

DO - 10.1016/j.immuni.2022.01.003

M3 - Article

SN - 1074-7613

VL - 55

SP - 423-441.e9

JO - Immunity

JF - Immunity

IS - 3

ER -

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

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