A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages

  1. Abigail J Morales
  2. Javier A Carrero
  3. Putzer J Hung
  4. Anthony T Tubbs
  5. Jared M Andrews
  6. Brian T Edelson
  7. Boris Calderon
  8. Cynthia L Innes
  9. Richard S Paules
  10. Jacqueline E Payton
  11. Barry P Sleckman  Is a corresponding author
  1. Weill Cornell Medical College, United States
  2. Washington University School of Medicine, United States
  3. National Institute of Environmental Health Sciences, United States

Abstract

Macrophages produce genotoxic agents, such as reactive oxygen and nitrogen species, that kill invading pathogens. Here we show that these agents activate the DNA damage response (DDR) kinases ATM and DNA-PKcs through the generation of double stranded breaks (DSBs) in murine macrophage genomic DNA. In contrast to other cell types, initiation of this DDR depends on signaling from the type I interferon receptor. Once activated, ATM and DNA-PKcs regulate a genetic program with diverse immune functions and promote inflammasome activation and the production of IL-1β and IL-18. Indeed, following infection with Listeria monocytogenes, DNA-PKcs-deficient murine macrophages produce reduced levels of IL-18 and are unable to optimally stimulate IFN-γ production by NK cells. Thus, genomic DNA DSBs act as signaling intermediates in murine macrophages, regulating innate immune responses through the initiation of a type I IFN-dependent DDR.

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Article and author information

Author details

  1. Abigail J Morales

    Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Javier A Carrero

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Putzer J Hung

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Anthony T Tubbs

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jared M Andrews

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Brian T Edelson

    Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Boris Calderon

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Cynthia L Innes

    Environmental Stress and Cancer Group, National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Richard S Paules

    Environmental Stress and Cancer Group, National Institute of Environmental Health Sciences, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jacqueline E Payton

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Barry P Sleckman

    Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, United States
    For correspondence
    bas2022@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8295-4462

Funding

National Institute of Allergy and Infectious Diseases (R01 AI047829)

  • Barry P Sleckman

National Institute of Allergy and Infectious Diseases (R01 AI074953)

  • Barry P Sleckman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were bred and maintained under specific pathogen-free conditions at the Washington University School of Medicine and Weill Cornell Medical College under protocol number 2015-0036. Mice were handled in accordance with the guidelines set forth by the Division of Comparative Medicine of Washington University and the Research Animal Research Center at Weill Cornell Medical College.

Copyright

© 2017, Morales et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Abigail J Morales
  2. Javier A Carrero
  3. Putzer J Hung
  4. Anthony T Tubbs
  5. Jared M Andrews
  6. Brian T Edelson
  7. Boris Calderon
  8. Cynthia L Innes
  9. Richard S Paules
  10. Jacqueline E Payton
  11. Barry P Sleckman
(2017)
A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages
eLife 6:e24655.
https://doi.org/10.7554/eLife.24655

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https://doi.org/10.7554/eLife.24655