A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages
- Weill Cornell Medical College, United States
- Washington University School of Medicine, United States
- 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.
Data availability
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DNA damage responses activate a multi-functional genetic program in murine bone marrow-derived macrophagesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE70467).
Article and author information
Author details
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.
Reviewing Editor
- Michel C Nussenzweig, The Rockefeller University, United States
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.
Version history
- Received: December 24, 2016
- Accepted: March 30, 2017
- Accepted Manuscript published: March 31, 2017 (version 1)
- Version of Record published: April 28, 2017 (version 2)
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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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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