Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock

Anthony Orvedahl, Michael R. McAllaster, Amy Sansone, Bria F. Dunlap, Chandni Desai, Ya Ting Wang, Dale R. Balce, Cliff J. Luke, Sanghyun Lee, Robert C. Orchard, Maxim N. Artyomov, Scott A. Handley, John G. Doench, Gary A. Silverman, Herbert W. Virgin

Research output: Contribution to journalArticle

Abstract

Host inflammatory responses must be tightly regulated to ensure effective immunity while limiting tissue injury. IFN gamma (IFNγ) primes macrophages to mount robust inflammatory responses. However, IFNγ also induces cell death, and the pathways that regulate IFNγ-induced cell death are incompletely understood. Using genome-wide CRISPR/Cas9 screening, we identified autophagy genes as central mediators of myeloid cell survival during the IFNγ response. Hypersensitivity of autophagy gene-deficient cells to IFNγ was mediated by tumor necrosis factor (TNF) signaling via receptor interacting protein kinase 1 (RIPK1)- and caspase 8-mediated cell death. Mice with myeloid cell-specific autophagy gene deficiency exhibited marked hypersensitivity to fatal systemic TNF administration. This increased mortality in myeloid autophagy gene-deficient mice required the IFNγ receptor, and mortality was completely reversed by pharmacologic inhibition of RIPK1 kinase activity. These findings provide insight into the mechanism of IFNγ-induced cell death via TNF, demonstrate a critical function of autophagy genes in promoting cell viability in the presence of inflammatory cytokines, and implicate this cell survival function in protection against mortality during the systemic inflammatory response.

Original languageEnglish (US)
Pages (from-to)16497-16506
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number33
DOIs
StatePublished - Jan 1 2019

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Autophagy
Myeloid Cells
Shock
Cell Death
Tumor Necrosis Factor-alpha
Receptor-Interacting Protein Serine-Threonine Kinases
Cell Survival
Genes
Protein Kinases
Mortality
Hypersensitivity
Clustered Regularly Interspaced Short Palindromic Repeats
Caspase 8
Immunity
Phosphotransferases
Macrophages
Genome
Cytokines
Wounds and Injuries

Keywords

  • Autophagy
  • Cell death
  • Interferon
  • Sepsis
  • TNF

ASJC Scopus subject areas

  • General

Cite this

Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock. / Orvedahl, Anthony; McAllaster, Michael R.; Sansone, Amy; Dunlap, Bria F.; Desai, Chandni; Wang, Ya Ting; Balce, Dale R.; Luke, Cliff J.; Lee, Sanghyun; Orchard, Robert C.; Artyomov, Maxim N.; Handley, Scott A.; Doench, John G.; Silverman, Gary A.; Virgin, Herbert W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 33, 01.01.2019, p. 16497-16506.

Research output: Contribution to journalArticle

Orvedahl, A, McAllaster, MR, Sansone, A, Dunlap, BF, Desai, C, Wang, YT, Balce, DR, Luke, CJ, Lee, S, Orchard, RC, Artyomov, MN, Handley, SA, Doench, JG, Silverman, GA & Virgin, HW 2019, 'Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 33, pp. 16497-16506. https://doi.org/10.1073/pnas.1822157116
Orvedahl, Anthony ; McAllaster, Michael R. ; Sansone, Amy ; Dunlap, Bria F. ; Desai, Chandni ; Wang, Ya Ting ; Balce, Dale R. ; Luke, Cliff J. ; Lee, Sanghyun ; Orchard, Robert C. ; Artyomov, Maxim N. ; Handley, Scott A. ; Doench, John G. ; Silverman, Gary A. ; Virgin, Herbert W. / Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 33. pp. 16497-16506.
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