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

Abstract
Data availability
Article and author information
Metrics

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

The following data sets were generated

1. Morales et al.
(2015) DNA damage responses activate a multi-functional genetic program in murine bone marrow-derived macrophages
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE70467).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70467

Article and author information

Author details

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

"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

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.